WO2022031407A1 - Gpr101 ligands for treating growth hormone-related disorders - Google Patents

Abstract

Disclosed herein are embodiments of a method comprising modifying GPR101 activity and/or growth hormone secretion using difeterol, vanoxeamine, and/or other compounds described herein. In particular embodiments, the compound embodiments disclosed herein are inverse agonists of GPR101 and thus can be used to treat diseases associated with GPR101 activity, such as hormonal-based growth disorders.

Description

GPR101 LIGANDS FOR TREATING GROWTH HORMONE-RELATED DISORDERS CROSS REFERENCE TO RELATED APPLICATION This application claims the benefit of the earlier filing date of U.S. Provisional Patent Application No.63/060,484, filed on August 3, 2020, the entirety of which is incorporated herein by reference. ACKNOWLEDGMENT OF GOVERNMENT SUPPORT This invention was made with government support under 1ZIAHD008920 awarded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The government has certain rights in the invention. FIELD The present disclosure relates to compound embodiments for use as GPR101 ligands and method embodiments for using the same to treat hormonal-based growth disorders. BACKGROUND Hormone secretion by the endocrine system glands is responsible for regulating many physiological processes in the body. The primary central regions that are responsible for controlling hormonal networks are the hypothalamus and the pituitary gland. Factors released by neurons in certain nuclei of the hypothalamus have stimulatory or inhibitory actions on the anterior pituitary gland cells. These anterior pituitary gland cells release hormones into the circulation, such as growth hormone (GH) and thyroid stimulating hormone, that, in turn, have potent effects on producing growth factors and other hormones in the liver, thyroid gland, etc. Hypothalamus and pituitary dysfunction can lead to profound disturbances in hormonal control of normal physiology. Underactivity of hypothalamic and pituitary hormone secretion can lead to syndromes of hypopituitarism, which vary in severity depending on the variety of hormone axes affected. For example, deficiency in hypothalamic and pituitary signals governing GHRH and GH release caused by genetic mutations can lead to forms of short stature or dwarfism. When tumors occur in endocrine cells, this can lead to disruption of normal hormonal secretion, either by destruction of the gland by non-hormone secreting tumor cells and concomitant under-secretion of hormones, or by overgrowth of hormone secreting cells in the tumor, leading to hyper-secretion of hormones. In the latter situation, the subject suffering from an endocrine tumor can suffer symptoms caused by growth of the tumor itself, combined with the effects of hormone over-secretion. In humans and other mammals, for example, a tumor of the pituitary gland may over-secrete active hormones GH or adrenocorticotropic hormone (ACTH), among others, leading to diseases, such as acromegaly-gigantism. Endocrine gland tumors are associated with significant morbidity and increased mortality when not controlled by available therapies. For tumors of the pituitary gland, medical, surgical and radiotherapies are used, either alone or in combination, to control disease. Therapeutics and methods for treating hormonal- based growth disorders, such as acromegaly, gigantism and other disorders of pituitary hormone hypersecretion, are needed in the art. SUMMARY Disclosed herein are embodiments of a method of using compound embodiments described herein as GPR101 ligands. In some embodiments, the method comprises exposing a biological sample expressing GPR101 or a subject expressing GPR101 to a compound selected from difeterol, vanoxeamine, a compound according to Formula I (described herein), a compound according to Formula II (described herein), or any combination thereof; or a stereoisomer, pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof. In some embodiments, the method comprises administering to a subject a therapeutically effective amount of a compound selected from difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, or any combination thereof, or a stereoisomer, pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof, to modify hormone production from the hypothalamus and/or the pituitary gland. Also disclosed are embodiments of a method comprising administering a therapeutically effective amount of difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, or a combination thereof, or a stereoisomer, pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof, to a subject having a pituitary gland tumor to thereby control the growth of the pituitary gland tumor. Pharmaceutical composition embodiments comprising difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, or any combination thereof, or a stereoisomer, pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof; and a pharmaceutically acceptable excipient, an adjuvant, an additional therapeutic agent, or any combination thereof also are disclosed. The foregoing and other objects and features of the present disclosure will become more apparent from the following detailed description, which proceeds with reference to the accompanying figures. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 is a graph of normalized HTRF Ratio (% basal) as a function of Log[difeterol concentration in M], illustrating results obtained from exposing HEK293AD-GPR101 cells and a control to difeterol at different concentrations and showing that difeterol exhibits a complete response curve in the HEK293AD- GPR101 cells, while an inactive curve was observed in control cells. FIG.2 is a graph of normalized HTRF Ratio (% basal) as a function of Log[vanoxeamine concentration in M], illustrating results obtained from exposing HEK293AD-GPR101 cells and a control to vanoxeamine at different concentrations and showing that vanoxeamine exhibits a good response curve in the HEK293AD-GPR101 cells, while an inactive curve was observed in control cells. FIG.3 is a graph of ATP content (nM) as a function of Log[compound concentration in M]), showing results obtained from evaluating cytotoxicity of difeterol and vanoxeamine using an ATP content assay after 6 hours using HEK293AD-GPR101 cells. FIG.4 is a graph of ATP content (nM) as a function of Log[compound concentration in M]), showing results obtained from evaluating cytotoxicity of difeterol and vanoxeamine using an ATP content assay after 24 hours using HEK293AD-GPR101 cells. FIG.5 is a graph of ATP content (nM) as a function of Log[compound concentration in M]), showing results obtained from evaluating cytotoxicity of difeterol using an ATP content assay after 24 hours using HEK293AD control cells. FIG.6 is a graph of ATP content (nM) as a function of Log[compound concentration in M]), showing results obtained from evaluating cytotoxicity of difeterol using an ATP content assay after 24 hours using HEK293AD-GPR101 cells. FIG.7 is a graph of cell number as a function of difeterol concentration showing results from exposing GH3 cells to difeterol at different concentrations after 24 hours and 48 hours. FIG.8 is a graph of prolactin concentration (ng/ml) as a function of difeterol concentration showing effects of different concentrations of difeterol on prolactin secretion from GH3 cells after 24 hours and 48 hours exposure time periods. FIG.9 is a graph of normalized prolactin concentration (ng/ml) as a function of difeterol concentration showing effects of different concentrations of difeterol on prolactin secretion from GH3 cells after 24 hours and 48 hours exposure time periods. SEQUENCES The nucleic and amino acid sequences listed in the accompanying sequence listing are shown using standard letter abbreviations for nucleotide bases, and three letter code for amino acids, as defined in 37 C.F.R. § 1.822. Only one strand of each nucleic acid sequence is shown, but the complementary strand is understood as included by any reference to the displayed strand. The Sequence Listing is submitted as an ASCII text file in the form of the file named “Sequence.txt” (~6.77 kb), which was created on July 7, 2021, which is incorporated by reference herein. In the accompanying sequence listing: SEQ ID NO: 1 is the amino acid sequence of GPR101. SEQ ID NO: 2 is the nucleic acid sequence of GPR101 mRNA. DETAILED DESCRIPTION I. Overview of Terms The following explanations of terms are provided to better describe the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure. As used herein, “comprising” means “including” and the singular forms “a” or “an” or “the” include plural references unless the context clearly dictates otherwise. The term “or” refers to a single element of stated alternative elements or a combination of two or more elements, unless the context clearly indicates otherwise. Unless explained otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting, unless otherwise indicated. Other features of the disclosure are apparent from the following detailed description and the claims. Unless otherwise indicated, all numbers expressing quantities of components, molecular weights, percentages, temperatures, times, and so forth, as used in the specification or claims are to be understood as being modified by the term “about.” Accordingly, unless otherwise indicated, implicitly or explicitly, the numerical parameters set forth are approximations that can depend on the desired properties sought and/or limits of detection under standard test conditions/methods. When directly and explicitly distinguishing embodiments from discussed prior art, the embodiment numbers are not approximates unless the word “about” is recited. Furthermore, not all alternatives recited herein are equivalents. Compound embodiments disclosed herein may contain one or more asymmetric elements such as stereogenic centers, stereogenic axes and the like, e.g., asymmetric carbon atoms, so that the chemical conjugates can exist in different stereoisomeric forms. These compound embodiments can be, for example, racemates or optically active forms. For compound embodiments with two or more asymmetric elements, these compound embodiments can additionally be mixtures of diastereomers. For compound embodiments having asymmetric centers, all optical isomers in pure form and mixtures thereof are encompassed by corresponding generic formulas unless context clearly indicates otherwise or an express statement excluding an isomer is provided. In these situations, the single enantiomers, i.e., optically active forms can be obtained by method known to a person of ordinary skill in the art, such as asymmetric synthesis, synthesis from optically pure precursors, or by resolution of the racemates. Resolution of the racemates can also be accomplished, for example, by conventional methods, such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column. All isomeric forms are contemplated herein regardless of the methods used to obtain them. All forms (for example solvates, optical isomers, enantiomeric forms, polymorphs, free compound and salts) of an active agent may be employed either alone or in combination. Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes (+/-) D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. To facilitate review of the various embodiments of the disclosure, the following explanations of specific terms are provided. Certain functional group terms include a symbol “-” which is used to show how the defined functional group attaches to, or within, the compound to which it is bound. Also, a dashed bond (i.e.,

as used in certain formulas described herein indicates an “optional” bond to a substituent or atom of the formula other than hydrogen in the sense that the bond (and in some embodiments, the substituent) may or may not be present. In any formulas comprising a dashed bond, if the optional bond and/or any corresponding substituent is not present, then the valency requirements of any atom(s) bound thereto is completed by a bond to a hydrogen atom. Solely by way of example, in the following formula, the dashed bond between the carbon atom adjacent to the NR group and the methyl (“Me”) group may be present, or this bond and methyl group may be absent and instead a bond to a hydrogen atom is present. Similarly, the dashed double bond between the other carbon atom adjacent to the NR group and the oxygen atom may be present, or this bond and the oxygen atom may be absent and instead a bond to two hydrogen atoms is present.

The symbol “ ” is used to indi in abbreviated structures/formulas provided herein. A person of ordinary skill in the art would recognize that the definitions provided below and the compounds and formulas included herein are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 different groups, and the like). Such impermissible substitution patterns are easily recognized by a person of ordinary skill in the art. In formulas and compounds disclosed herein, a hydrogen atom is present and completes any formal valency requirements (but may not necessarily be illustrated) wherever a functional group or other atom is not illustrated. For example, a phenyl ring that is drawn as comprises a hydrogen atom attached to each carbon atom of the phenyl ring other than the

“a” car en though such hydrogen atoms are not illustrated. Any functional group disclosed herein and/or defined above can be substituted or unsubstituted, unless otherwise indicated herein. Any compound embodiment described herein can be deuterated or not deuterated, unless otherwise indicated herein. Suitable positions at which a compound can be deuterated are readily recognized by people of ordinary skill in the art. A person of ordinary skill in the art will appreciate that compounds may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism, and/or optical isomerism. For example, certain disclosed compounds can include one or more chiral centers and/or double bonds and as a consequence can exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof, such as racemic mixtures. As another example, certain disclosed compounds can exist in several tautomeric forms, including the enol form, the keto form, and mixtures thereof. As the various compound names, formulae and compound drawings within the specification and claims can represent only one of the possible tautomeric, conformational isomeric, optical isomeric, or geometric isomeric forms, a person of ordinary skill in the art will appreciate that the disclosed compounds encompass any tautomeric, conformational isomeric, optical isomeric, and/or geometric isomeric forms of the compounds described herein, as well as mixtures of these various different isomeric forms. Mixtures of different isomeric forms, including mixtures of enantiomers and/or stereoisomers, can be separated to provide each separate enantiomers and/or stereoisomer using techniques known to those of ordinary skill in the art, particularly with the benefit of the present disclosure. In cases of limited rotation, e.g. around the amide bond or between two directly attached rings such as pyridinyl rings, biphenyl groups, and the like, atropisomers are also possible and are also specifically included in the compounds disclosed herein. In any embodiments, any or all hydrogens present in the compound, or in a particular group or moiety within the compound, may be replaced by a deuterium or a tritium. Thus, a recitation of alkyl includes deuterated alkyl, where from one to the maximum number of hydrogens present may be replaced by deuterium. For example, methyl refers to both CH3 or CH3 wherein from 1 to 3 hydrogens are replaced by deuterium, such as in CDxH3-x. As used herein, the term “substituted” refers to all subsequent modifiers in a term, for example in the term “substituted aliphatic-aromatic,” substitution may occur on the “aliphatic” portion, the “aromatic” portion or both portions of the aliphatic-aromatic group. “Substituted,” when used to modify a specified group or moiety, means that at least one, and perhaps two or more, hydrogen atoms of the specified group or moiety is independently replaced with the same or different substituent groups. In a particular embodiment, a group, moiety, or substituent may be substituted or unsubstituted, unless expressly defined as either “unsubstituted” or “substituted.” Accordingly, any of the functional groups specified herein may be unsubstituted or substituted unless the context indicates otherwise or a particular structural formula precludes substitution. In particular embodiments, a substituent may or may not be expressly defined as substituted but is still contemplated to be optionally substituted. For example, an “aliphatic” or a “cyclic” moiety may be unsubstituted or substituted, but an “unsubstituted aliphatic” or an “unsubstituted cyclic” is not substituted. In one embodiment, a group that is substituted has at least one substituent up to the number of substituents possible for a particular moiety, such as 1 substituent, 2 substituents, 3 substituents, or 4 substituents. Any group or moiety defined herein can be connected to any other portion of a disclosed structure, such as a parent or core structure, as would be understood by a person of ordinary skill in the art, such as by considering valence rules, comparison to exemplary species, and/or considering functionality, unless the connectivity of the group or moiety to the other portion of the structure is expressly stated, or is implied by context. Administering (or Administration or Administer): Any means for introducing a compound embodiment according to the present disclosure, including any pharmaceutical composition thereof, into a subject or exposing a biological sample to such compound embodiment and/or any pharmaceutical composition thereof. Exemplary modes of administration can include, but are not limited to, oral, buccal, sublingual, nasal, pulmonary, ophthalmic, transdermal, transmucosal, subcutaneous, intratumoral, iontophoretic, intraperitoneal, intravenous, intramuscular injection, transplacental transfer, and/or lactation. Aliphatic: A hydrocarbon group having at least one carbon atom to 50 carbon atoms (C_1-50), such as one to 25 carbon atoms (C_1-25), or one to ten carbon atoms (C_1-10), and which includes alkanes (or alkyl), alkenes (or alkenyl), alkynes (or alkynyl), including cyclic versions thereof, and further including straight- and branched-chain arrangements, and all stereo and position isomers as well. Aliphatic groups may be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. Alkenyl: An unsaturated monovalent hydrocarbon having at least two carbon atom to 50 carbon atoms (C_2-50), such as two to 25 carbon atoms (C_2-25), or two to ten carbon atoms (C_2-10), and at least one carbon-carbon double bond, wherein the unsaturated monovalent hydrocarbon can be derived from removing one hydrogen atom from one carbon atom of a parent alkene. An alkenyl group can be branched, straight-chain, cyclic (e.g., cycloalkenyl), cis, or trans (e.g., E or Z). Alkenyl groups may be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. Alkyl: A saturated monovalent hydrocarbon having at least one carbon atom to 50 carbon atoms (C_1-50), such as one to 25 carbon atoms (C_1-25), or one to ten carbon atoms (C_1-10), wherein the saturated monovalent hydrocarbon can be derived from removing one hydrogen atom from one carbon atom of a parent compound (e.g., alkane). An alkyl group can be branched, straight-chain, or cyclic (e.g., cycloalkyl). Alkyl groups may be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. Alkynyl: An unsaturated monovalent hydrocarbon having at least two carbon atom to 50 carbon atoms (C_2-50), such as two to 25 carbon atoms (C_2-25), or two to ten carbon atoms (C_2-10), and at least one carbon-carbon triple bond, wherein the unsaturated monovalent hydrocarbon can be derived from removing one hydrogen atom from one carbon atom of a parent alkyne. An alkynyl group can be branched, straight- chain, or cyclic (e.g., cycloalkynyl). Alkenyl groups may be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. Carrier: An excipient that serves as a component capable of delivering a compound embodiment described herein. In some embodiments, a carrier can be a suspension aid, solubilizing aid, or aerosolization aid. In general, the nature of the carrier will depend on the particular mode of administration being employed. For instance, parenteral formulations usually comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle. In some examples, the pharmaceutically acceptable carrier may be sterile to be suitable for administration to a subject (for example, by parenteral, intramuscular, or subcutaneous injection). In addition to biologically-neutral carriers, pharmaceutical formulations to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate. GPR101 (or GPR101 protein, GPCR, or orphan G Protein Coupled Receptor): A protein that is highly expressed in hypothalamus and is predicted to couple to G_s, a potent activator of adenylyl cyclase. GPR101 protein is encoded by the gene GPR101. Growth hormone releasing hormone (or GHRH): A peptide belonging to the secretin glucagon family of neuroendocrine and gastrointestinal hormones. Human GHRH (hGHRH) peptide is comprised of 44 amino acid residues. The best known site of production of GHRH is the hypothalamus. hGHRH is also produced by human malignant tissues (cancers) of diverse origin. Hypothalamic GHRH is an endocrine releasing hormone that, acting through specific GHRH receptors on the pituitary, which regulates the secretion of pituitary growth hormone (GH). Halo (or halide or halogen): Fluoro, chloro, bromo, iodo. In some embodiments, halo can also include astatine. Haloalkyl: An alkyl group wherein one or more hydrogen atoms, such as one to 10 hydrogen atoms, independently is replaced with a halogen atom, such as fluoro, bromo, chloro, or iodo. Haloalkyl groups can be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic, or an organic functional group. In an independent embodiment, haloalkyl can be a CX3 group, wherein each X independently can be selected from fluoro, bromo, chloro, or iodo. Pharmaceutically Acceptable Excipient: A substance, other than a compound that is included in a composition of the compound. As used herein, an excipient may be incorporated within particles of a pharmaceutical composition, or it may be physically mixed with particles of a pharmaceutical composition. An excipient also can be in the form of a solution, suspension, emulsion, or the like. An excipient can be used, for example, to dilute an active agent and/or to modify properties of a pharmaceutical composition. Excipients can include, but are not limited to, antiadherents, binders, coatings, enteric coatings, disintegrants, flavorings, sweeteners, colorants, lubricants, glidants, sorbents, preservatives, adjuvants, carriers or vehicles. Excipients may be starches and modified starches, cellulose and cellulose derivatives, saccharides and their derivatives such as disaccharides, polysaccharides and sugar alcohols, protein, synthetic polymers, crosslinked polymers, antioxidants, amino acids or preservatives. Exemplary excipients include, but are not limited to, magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose, starches, hydroxypropyl cellulose, hydroxypropyl methylcellulose, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS, or TPGS), carboxy methyl cellulose, dipalmitoyl phosphatidyl choline (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methyl paraben, propyl paraben, sugar, silica, talc, magnesium carbonate, sodium starch glycolate, tartrazine, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulphite or lanolin. In independent embodiments, water is not intended as a pharmaceutically acceptable excipient. Pharmaceutically Acceptable Salt: Pharmaceutically acceptable salts of a compound described herein that are derived from a variety of organic and inorganic counter ions as will be known to a person of ordinary skill in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like. “Pharmaceutically acceptable acid addition salts” are a subset of “pharmaceutically acceptable salts” that retain the biological effectiveness of the free bases while formed by acid partners. In particular, the disclosed compound embodiments form salts with a variety of pharmaceutically acceptable acids, including, without limitation, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, phosphonic acid, and the like, as well as organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzene sulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. “Pharmaceutically acceptable base addition salts” are a subset of “pharmaceutically acceptable salts” that are derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Exemplary salts are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, (1r,4r)- 4-(aminomethyl)cyclohexane-1-carboxylic acid, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66:1-19 which is incorporated herein by reference.) Subject: A living being, with particular embodiments being mammals and other animals. In particular embodiments, the subject is a human. In other embodiments, the subject is an animal, such as a livestock animal, a domesticated animal, or the like. Method embodiments disclosed herein therefore are applicable to human therapy, veterinary applications, and/or animal production. Livestock includes poultry (e.g., chickens, goose, duck, turkey, pheasant, and the like); swine; cattle (for beef and/or dairy production); sheep; and goats. Therapeutically Effective Amount: An amount of compound embodiment disclosed herein, or an amount of a pharmaceutical composition thereof, that is sufficient cause the desired effect, such as to treat a condition or disease of interest. “Treating” or “treatment” as used herein concerns treatment of a disease or condition of interest in a patient or subject, particularly a human having the disease or condition of interest, and includes by way of example, and without limitation: (i) preventing the disease or condition from occurring in a patient or subject, in particular, when such patient or subject is predisposed to the condition but has not yet been diagnosed as having it; (ii) inhibiting the disease or condition, for example, arresting or slowing its development; (iii) relieving the disease or condition, for example, causing diminution of a symptom or regression of the disease or condition or a symptom thereof; or (iv) stabilizing the disease or condition. As used herein, the terms “disease” and “condition” can be used interchangeably or can be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been determined) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, where a more or less specific set of symptoms have been identified by clinicians. X-linked acrogigantism (X-LAG) syndrome: A form of inheritable pituitary gigantism that begins in early childhood and is usually associated with very elevated growth hormone (GH) and prolactin secretion by mixed pituitary adenomas. Microduplications on chromosome Xq26.3 that include the gene GPR101 underlie the genetic etiology of X-LAG syndrome. II. Introduction Hormone secretion by the endocrine system glands is responsible for regulating many physiological processes in the body. The primary central regions that are responsible for controlling hormonal networks are the hypothalamus and the pituitary gland. Factors released by neurons in certain nuclei of the hypothalamus have stimulatory or inhibitory actions on the anterior pituitary gland cells. These anterior pituitary gland cells release hormones into the circulation, such as growth hormone (GH) and thyroid stimulating hormone, that, in turn, have potent effects on producing growth factors and other hormones in the liver, thyroid gland, etc. Controlling these systems can be important for normal development across multiple animal species, including humans. For instance, human GH secretion has a pattern that is pulsatile and diurnal: peaks of GH occur every two to four hours, usually at night. GH secretion is regulated by hormonal and biochemical factors. GH releasing hormone (GHRH) and somatostatin play opposite roles in modulating GH secretion. GHRH acts as a stimulator and somatostatin acts as an inhibitor. And, GPR101 is part of this dual signal machinery. GHRH is released by neurons in the median eminence and the infudibular nucleus of the hypothalamus and this pulsatile release of GHRH is a potent stimulator of GH secretion from the anterior pituitary. GH stimulates IGF-I release from the liver and other tissues, which then feeds back to stimulate somatostatin and inhibit GHRH under normal circumstances. Regulating GHRH receptor (GHRH-R) and somatostatin receptor (SSTR) concentrations in the pituitary gland plays a part in controlling this system, as do the actions of other hormones, such as estrogen and testosterone. Hypothalamus and pituitary dysfunction can lead to profound disturbances in hormonal control of normal physiology. Underactivity of hypothalamic and pituitary hormone secretion can lead to syndromes of hypopituitarism, which vary in severity depending on the variety of hormone axes affected. For example, deficiency in hypothalamic and pituitary signals governing GHRH and GH release caused by genetic mutations can lead to forms of short stature or dwarfism. Replacement therapy typically is required in these conditions depending on the deficient hormones. Pituitary gigantism is a very recognizable but rare disorder. Patients with pituitary gigantism develop growth hormone (GH) excess from a pituitary tumor before closure of epiphyseal growth plates. The etiology of pediatric or adolescent pituitary tumors in general, and pituitary gigantism in particular, remains relatively obscure, with about 50% of cases of the latter having no known genetic cause. The most frequent known genetic cause is aryl hydrocarbon receptor interacting protein gene (AIP) mutations. X-linked acrogigantism (X-LAG) syndrome is a form of inheritable pituitary gigantism that begins in early childhood and is usually associated with very elevated growth hormone (GH) and prolactin secretion by mixed pituitary adenomas. Microduplications on chromosome Xq26.3 that include the gene GPR101 underlie the genetic etiology of X-LAG syndrome. X-LAG syndrome is characterized by gigantism occurring during infancy. X-LAG syndrome patients develop pituitary adenomas/hyperplasia and greatly elevated growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels that are usually accompanied by hyperprolactinemia. Unlike other forms of pituitary gigantism due to single gene mutations/deletions, the underlying abnormality in X-LAG syndrome is a microduplication in chromosome Xq26.3 that includes the orphan G-protein coupled receptor (GPCR) gene, GPR101. Subjects with X-LAG syndrome usually develop pituitary macroadenomas, while a few have hyperplasia alone or in conjunction with adenoma. Somatic growth is orchestrated by a complex hormonal crosstalk involving the hypothalamus, pituitary, and peripheral tissues. Genetic disorders that affect this network can lead to increased secretion of growth hormone, which results in acromegaly. If the excess in growth hormone occurs before epiphyseal fusion, the result can be gigantism. Nonsyndromic gigantism is most frequently caused by pituitary adenomas occurring as familial isolated pituitary adenomas or sporadically, usually as a result of mutations in the gene encoding aryl hydrocarbon receptor–interacting protein (AIP). Hypopituitarism results from diminished hormone secretion by the pituitary gland. When tumors occur in endocrine cells, this can lead to disruption of normal hormonal secretion, either by destruction of the gland by non-hormone secreting tumor cells and concomitant under-secretion of hormones, or by overgrowth of hormone secreting cells in the tumor, leading to hyper-secretion of hormones. In the latter situation, the subject suffering from an endocrine tumor can suffer symptoms caused by growth of the tumor itself, combined with the effects of hormone over-secretion. In humans and other mammals, for example, a tumor of the pituitary gland may over-secrete active hormones GH or adrenocorticotropic hormone (ACTH), among others, leading to diseases, such as acromegaly-gigantism. Endocrine gland tumors are associated with significant morbidity and increased mortality when not controlled by available therapies. For tumors of the pituitary gland, medical, surgical and radiotherapies typically are used, either alone or in combination, to control disease. For example, GH hypersecretion by a pituitary tumor in a subject that has not finished pubertal growth (such that bone growth plates have not yet fused) can cause physical overgrowth, including increased height, leading to a disease called gigantism. In adults, similar GH secreting pituitary tumors cause a disease called acromegaly in which an overgrowth deformation of the face and extremities is accompanied by important morbidities of the metabolic system and cardiovascular system, among others. Therapeutics for treating hormonal-based growth disorders, such as acromegaly, gigantism, syndromes of hypopituitarism, and other disorders of pituitary hormone hypersecretion, are needed in the art. The present disclosure concerns methods of using difeterol, vanoxeamine, and/or other compounds described herein, as ligands for GPR101, which in turn facilitates using such compounds for regulating GH secretion. As such, these compound embodiments can be used in method embodiments for treating disorders resulting from increases and/or decreases in GH secretion. III. Compound and Method Embodiments Disclosed herein are embodiments of a method of using difeterol, vanoxeamine, and/or compounds having a structure satisfying Formula I or Formula II (as described below) as ligands for GPR101. The structures of difeterol and vanoxeamine are provided below.

P lso can be used in method embodiments disclosed herein. In particular embodiments, the pharmaceutically acceptable salt can be selected from a (1r,4r)-4-(aminomethyl)cyclohexane-1-carboxylic acid salt, a fumaric acid salt, an oxalic acid salt, a sodium salt, or a hydrochloric acid salt. In some embodiments, the compound can have a structure according to Formula I illustrated below, including any pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, and/or prodrug thereof.

With reference to F y is halogen, NO₂, or haloalkyl; each Y independently is O or CH₂; R is hydrogen or aliphatic; n is an integer selected from 0, 1, or 2; and each of m, m’, and m’’ independently is an integer selected from 0 to 5. In particular embodiments, each of X, X’, and X’’ independently is F, Cl, Br, I, NO₂, or CF₃; each Y independently is a bond, O or CH₂; R is hydrogen or lower aliphatic; n is an integer selected from 0, 1, or 2; and each of m, m’, and m’’ independently is an integer selected from 0 or 1. In particular disclosed embodiments, each of X and X’ is F and each F atom is bound at the para position on the ring, and each X’’ is nitro bound at the para position, or CF₃ bound at the meta position. In particular embodiments, if n is 0, then Y is not present and the carbon atoms otherwise bound to Y are instead bound to one or more hydrogen atoms. In other embodiments, n is 1, then Y is present and is a bond, thereby forming an oxetane ring. In yet other embodiments, if n is 2, then one Y is oxygen and the other Y is CH₂. In exemplary embodiments, R is hydrogen or methyl and each of m, m’, and m’’ independently is 0 or 1. In some embodiments, the compound can have a structure according to any one of Formulas IA, IB, or IC, including any pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, and/or prodrug thereof. With reference to these formulas, the illustrated X, X’, X’’, R, m, m’, and m’’ groups can be as recited above for Formula I.

Formula IC In some such embodiments, the compound can have a structure according to Formula II illustrated below, including any pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, and/or prodrug thereof.

Formula II With reference to Formula II, each of Z, Z’, and Z’’ independently is halogen, NO₂, or haloalkyl; and each of p, p’, and p’’ independently is an integer selected from 0 to 5, such as 0, 1, 2, 3, 4, or 5. In particular embodiments, each of Z, Z’, and Z’’ independently is F, Cl, Br, I, NO₂, or CF₃ and each of p, p’, and p’’ independently is 0 or 1. In exemplary embodiments, each of Z and Z’ is F, if p and p’ are 1; and Z’’ is nitro or CF₃ if p’’ is 1. In particular embodiments, the Z, Z’, and/or Z’’ groups are bound at the para or meta positions. In particular embodiments of Formulas I and II, the compound can be selected from any of the compounds illustrated below, any pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, solvate, and/or prodrug thereof.

In some embodiments, the compound can be selected from the following, including any pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, and/or prodrug thereof: 2-((2-(benzhydryloxy)ethyl)(methyl)amino)-1-phenylpropan-1-ol; (S)-2-((2-(benzhydryloxy)ethyl)(methyl)amino)-1-phenylethan-1-ol; (R)-2-((2-(benzhydryloxy)ethyl)(methyl)amino)-1-phenylethan-1-ol; 2-((2-(benzhydryloxy)ethyl)(methyl)amino)-1-phenylethan-1-ol; 2-((2-(benzhydryloxy)ethyl)amino)-1-(4-nitrophenyl)ethan-1-ol; (S)-2-((2-(benzhydryloxy)ethyl)amino)-1-(4-nitrophenyl)ethan-1-ol; (R)-2-((2-(benzhydryloxy)ethyl)amino)-1-(4-nitrophenyl)ethan-1-ol; 2-(benzhydryloxy)-N-(2-(3-fluorophenyl)-2-hydroxyethyl)acetamide; (S)-2-(benzhydryloxy)-N-(2-(3-fluorophenyl)-2-hydroxyethyl)acetamide; (R)-2-(benzhydryloxy)-N-(2-(3-fluorophenyl)-2-hydroxyethyl)acetamide; 2-(benzhydryloxy)-N-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)acetamide; (S)-2-(benzhydryloxy)-N-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)acetamide; (R)-2-(benzhydryloxy)-N-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)acetamide; N-(1-hydroxy-1-phenylpropan-2-yl)-3,3-diphenyloxirane-2-carboxamide; (S)-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-3,3-diphenyloxirane-2-carboxamide; (S)-N-((1R,2R)-1-hydroxy-1-phenylpropan-2-yl)-3,3-diphenyloxirane-2-carboxamide; (S)-N-((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)-3,3-diphenyloxirane-2-carboxamide; (S)-N-((1R,2S)-1-hydroxy-1-phenylpropan-2-yl)-3,3-diphenyloxirane-2-carboxamide; (R)-N-((1R,2R)-1-hydroxy-1-phenylpropan-2-yl)-3,3-diphenyloxirane-2-carboxamide; (R)-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-3,3-diphenyloxirane-2-carboxamide; (R)-N-((1R,2S)-1-hydroxy-1-phenylpropan-2-yl)-3,3-diphenyloxirane-2-carboxamide; (R)-N-((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)-3,3-diphenyloxirane-2-carboxamide; 2-(((2,2-diphenyl-1,3-dioxolan-4-yl)methyl)(methyl)amino)-1-phenylpropan-1-ol; (1R,2S)-2-(((2,2-diphenyl-1,3-dioxolan-4-yl)methyl)(methyl)amino)-1-phenylpropan-1-ol; (1S,2S)-2-(((2,2-diphenyl-1,3-dioxolan-4-yl)methyl)(methyl)amino)-1-phenylpropan-1-ol; (1R,2R)-2-(((2,2-diphenyl-1,3-dioxolan-4-yl)methyl)(methyl)amino)-1-phenylpropan-1-ol; (1S,2R)-2-(((2,2-diphenyl-1,3-dioxolan-4-yl)methyl)(methyl)amino)-1-phenylpropan-1-ol; 2-((2-(bis(4-fluorophenyl)methoxy)ethyl)amino)-1-phenylpropan-1-ol; (1S,2R)-2-((2-(bis(4-fluorophenyl)methoxy)ethyl)amino)-1-phenylpropan-1-ol; (1R,2S)-2-((2-(bis(4-fluorophenyl)methoxy)ethyl)amino)-1-phenylpropan-1-ol; (1R,2R)-2-((2-(bis(4-fluorophenyl)methoxy)ethyl)amino)-1-phenylpropan-1-ol; (1S,2S)-2-((2-(bis(4-fluorophenyl)methoxy)ethyl)amino)-1-phenylpropan-1-ol; 2-((2-(bis(4-fluorophenyl)methoxy)ethyl)(methyl)amino)-1-phenylpropan-1-ol; (1R,2S)-2-((2-(bis(4-fluorophenyl)methoxy)ethyl)(methyl)amino)-1-phenylpropan-1-ol; (1S,2R)-2-((2-(bis(4-fluorophenyl)methoxy)ethyl)(methyl)amino)-1-phenylpropan-1-ol; (1R,2R)-2-((2-(bis(4-fluorophenyl)methoxy)ethyl)(methyl)amino)-1-phenylpropan-1-ol; (1S,2S)-2-((2-(bis(4-fluorophenyl)methoxy)ethyl)(methyl)amino)-1-phenylpropan-1-ol; 1-(2-(benzhydryloxy)ethyl)-4-(3-phenylpropyl)piperazine; 1-(2-(benzhydryloxy)ethyl)-4-(3-(4-nitrophenyl)propyl)piperazine; 1-(2-(benzhydryloxy)ethyl)-4-(3-(3-fluorophenyl)propyl)piperazine; 1-(2-(benzhydryloxy)ethyl)-4-(3-(3-(trifluoromethyl)phenyl)propyl)piperazine; 1-(2-(bis(4-fluorophenyl)methoxy)ethyl)-4-(3-phenylpropyl)piperazine; 2-((2-(benzhydryloxy)ethyl)(methyl)amino)-1-phenylpropan-1-ol phosphonic acid; 2-((2-(benzhydryloxy)ethyl)(methyl)amino)-1-phenylpropan-1-ol hydrochloric acid; (1S,2R)-2-((2-(bis(4-fluorophenyl)methoxy)ethyl)amino)-1-phenylpropan-1-ol hydrochloric acid; (1R,2R)-2-((2-(bis(4-fluorophenyl)methoxy)ethyl)amino)-1-phenylpropan-1-ol oxalic acid; 2-((2-(benzhydryloxy)ethyl)amino)-1-(4-nitrophenyl)ethan-1-ol fumaric acid; 2-((2-(benzhydryloxy)ethyl)(methyl)amino)-1-phenylpropan-1-ol phosphate; (1R,2S)-2-(((2,2-diphenyl-1,3-dioxolan-4-yl)methyl)(methyl)amino)-1-phenylpropan-1-ol hydrochloric acid; or 2-((2-(benzhydryloxy)ethyl)(methyl)amino)-1-phenylethan-1-ol oxalic acid. In some embodiments, the compound embodiments described herein can have one or more of the following activities: (i) selectively decreasing or blocking binding of a ligand to GPR101 protein; (ii) selectively decreasing or blocking binding of a fragment of gonadotropin-releasing hormone, such as GnRH- (1-5), to GPR101 protein; (iii) reducing or blocking cAMP pathway activation by GPR101; and/or (iv) downregulating GPR101 mRNA, protein and/or activity. In some other embodiments, the compound embodiments described herein also may generally downregulate GPR101 mRNA, protein and/or activity, which can include reducing or blocking GPR101 mRNA transcription, translation, transport, GPR101 protein transport, folding, and/or modification. In some embodiments, the compounds are antagonists of GPR101 In particular embodiments, the compound embodiments disclosed herein are inverse agonists of GPR101. In some embodiments, the GPR101 can be GPR101 that is expressed in the hypothalamus or it can be GPR101 that is expressed in an abnormal pituitary gland, such as a tumorous pituitary gland, a hyperplastic pituitary gland, or both. In some such embodiments, the method can comprise exposing a biological sample expressing GPR101 or a subject expressing GPR101 to a therapeutically effective amount of a compound embodiment described herein, or a pharmaceutical composition thereof. In particular embodiments, the method comprises exposing the biological sample expressing GPR101 or the subject expressing GPR101 to a therapeutically effective amount of difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, or a combination thereof, or any pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, and/or prodrug thereof. In such embodiments, the difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, or a combination thereof (or any pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, and/or prodrug thereof) modifies the activity of the GPR101. In some embodiments, the compound inhibits GPR101 activity. In some other embodiments, the compound decreases GPR101 activity. The biological sample can be an ex vivo biological sample, an in vitro sample, or the like. In some embodiments, the biological sample comprises a cell, such as a HEK293AD cell, a HEK293AD-GPR101 cell, a GH3 cell, or the like. The subject can be a human subject or another animal expressing GPR101. In some embodiments, the subject expressing GPR101 can have, or be prone to developing, a disease involving irregular GH secretion. In some such embodiments, the disease involving irregular GH secretion can be the result of too little GH secretion and thus the compound can be administered modify the amount of GH secretion by increasing or stimulating GH secretion. In yet other embodiments, the disease involving irregular GH secretion can be the result GH hypersecretion and thus the compound can be administered to modify GH secretion by decreasing or inhibiting GH secretion. In some embodiments, the subject can exhibit irregular prolactin secretion, in which cases the compound can be administered to modify the prolactin secretion, such as to increase or decrease it. In yet additional embodiments, the subject expressing GPR101 can have an abnormal pituitary gland, such as a tumorous pituitary gland, a hyperplastic pituitary gland, or both. In some particular embodiments, the subject expressing GPR101 can have, or be prone to developing, a disease selected from acromegaly, gigantism, hypopituitarism, dwarfism, short stature, or X-linked acrogigantism (or X-LAG syndrome). In yet other embodiments, the subject can be a non-human animal in which body size and/or body mass is to be increased. Also disclosed are method embodiments, wherein a therapeutically effective amount of a compound of the present disclosure is administered to a subject having, or prone to developing, a disease associated with GPR101. The compound can be difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, or a combination thereof, or any pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, and/or prodrug thereof. In some such embodiments, the disease associated with GPR101 can involve over-secretion or under-secretion of GH from the hypothalamus. In other embodiments, the disease associated with GPR101 can involve over-secretion of GH resulting from GPR101 expression in a tumorous or hyperplastic pituitary gland. In particular embodiments, the subject has, or is prone to developing, acromegaly, gigantism, hypopituitarism, dwarfism, short stature, or X-LAG syndrome. In other embodiments, the method can comprise administering a therapeutically effective amount of difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, or a combination thereof, or any pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, and/or prodrug thereof, to a subject having a pituitary gland tumor to thereby control the growth of the pituitary gland tumor. Also disclosed herein are method embodiments for treating a disease selected from acromegaly, gigantism (e.g., pituitary gigantism, nonsyndromic gigantism, or the like), hypopituitarism, dwarfism, short stature, or X-LAG syndrome. These method embodiments can comprise administering difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, or any pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, and/or prodrug thereof, to a subject expressing GPR101 in the hypothalamus or an abnormal pituitary gland. Also disclosed are method embodiments comprising administering a compound embodiment of the present disclosure to livestock to thereby increase body mass and/or body size of the livestock. In such embodiments, administering the compound embodiment, such as difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, or a combination thereof, or any pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, and/or prodrug thereof, can increase GPR101 activity and hormone secretion. This activity increases body mass and/or body size of the livestock, leading to higher meat production yields. In yet some additional embodiments, the livestock can be a transgenic animal comprising, as an expressed transgene, a gene encoding GPR101 or overexpressing endogenous GPR101 gene. The GPR101 gene expressed as transgene in the transgenic animal may be any animal, such as a mammalian GPR101 gene (e.g., human GPR101 gene). In an alternative embodiment, the transgenic animal is altered by genetic engineering, wherein the regulation of the expression of the respective endogenous GPR101 gene(s) is modified in that way that the endogenous gene is expressed at a higher rate compared to the wild-type or unmodified gene. Either of these modifications increases growth hormone secretion, leading to increased body mass and/or body size of the livestock, which in turn leads to higher meat production yields. In any method embodiments disclosed herein, the compound can be administered neat, individually or in combination with one or more other compound embodiments; or as a pharmaceutical composition as disclosed herein that comprises one or more compound embodiments. Therapeutically effective amounts of the compound embodiments disclosed herein can be an amount that is sufficient to achieve a therapeutically beneficial effect. In some embodiments, the therapeutically effective amount of the compound embodiments can be determined by methods that would be known to those of ordinary skill in the art with the benefit of the present disclosure. Such amounts may vary according to the particular compound(s) within any pharmaceutical composition, the concentration of the compound(s) in any such pharmaceutical composition, the frequency of administration, the severity of disease to be treated, and subject details, such as age, weight, and immune condition. In some embodiments, dosages ranging from 50 mg to 10000 mg (or more) of a pharmaceutical composition embodiment or a compound embodiment per kilogram of body weight (mg/kg) can be administered, such as 100 mg/kg to 1000 mg/kg or more, 150 mg/kg to 1000 mg/kg or more, 200 mg/kg to 1000 mg/kg or more, 250 mg/kg to 1000 mg/kg or more, 500 mg/kg to 1000 mg/kg or more, or 750 mg/kg to 1000 mg/kg or more. In yet additional embodiments, the dosage can range from 5 mg/kg to 25 mg/kg (or more) of a pharmaceutical composition embodiment or a compound embodiment, such as 10 mg/kg to 25 mg/kg or more, or 15 mg/kg to 25 mg/kg or more, or 20 mg/kg to 25 mg/kg or more. The subject according to the method embodiments disclosed herein can be exposed to the compound using any suitable administration route, such as, but not limited to, oral, buccal, sublingual, nasal, pulmonary, ophthalmic, transdermal, transmucosal, subcutaneous, intratumoral, iontophoretic, intraperitoneal, intravenous, intramuscular injection, transplacental transfer, and/or lactation routes. In particular embodiments, the compound(s) are administered as a liquid pharmaceutical composition using an intravenous, subcutaneous, intramuscular, intraperitoneal, and/or intratumorally route of administration. IV. Pharmaceutical Composition Embodiments Also disclosed are pharmaceutical composition embodiments comprising any one or more of the compound embodiments described herein. In some embodiments, the pharmaceutical composition can comprise a single compound, such as difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, or a plurality of compounds, such as a combination of any one or more of difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, wherein each compound in the plurality of compounds is different. In some embodiments, the pharmaceutical composition can comprise a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, or prodrug of the one or more compounds. Pharmaceutical composition embodiments comprising one or more of the compound embodiments disclosed herein typically comprise the compound or plurality of compounds in a singular or total amount of from greater than 0% up to 99% total weight percent. In some embodiments, pharmaceutical compositions comprising one or more of the compound embodiments disclosed herein comprise from greater than 0 wt% to 95 wt%, such as 0.001 wt% to 95% wt%, or 0.01 wt% to 95 wt%, or 0.1 wt% to 95 wt%, or 1 wt% to 95 wt% of the compound (singularly or in total) based on the total weight percent of the pharmaceutical composition. In some embodiments, pharmaceutical compositions comprising one or more of the compound embodiments disclosed herein comprise from greater than 0 wt% to 95 wt%, such as greater than 0 wt% to 90% wt%, or greater than 0 wt% to 85 wt%, or greater than 0 wt% to 80 wt%, or greater than 0 wt% to 75 wt%, or greater than 0 wt% to 70 wt%, or greater than 0 wt% to 65 wt%, or greater than 0 wt% to 60 wt%, or greater than 0 wt% to 55 wt%, or greater than 0 wt% to 50 wt% or lower of the compound based on the total weight percent of the pharmaceutical composition. The remaining weight percent of the pharmaceutical composition can be made up of any one or more of the other compositional components described below. Pharmaceutical composition embodiments can further comprise a pharmaceutically-acceptable excipient, such as, but not limited to, an adjuvant, a carrier, a stabilizer, or combinations thereof. The pharmaceutical composition also can include additional components, such as diluents, fillers, binding agents, moisturizing agents, preservatives, acids, and the like, and any and all combinations thereof. In some embodiments, the pharmaceutical composition can further comprise one or more additional compounds, such as therapeutic agents useful for the disorder or condition being treated. Exemplary therapeutic agents (that is, therapeutic agents other than the compound embodiments described herein) that can be used for treating the diseases/conditions described herein include those that would be recognized by a person of ordinary skill in the art, with the benefit of this disclosure, as being suitable for treating such diseases/conditions. In particular embodiments, the therapeutic agent may be a monoclonal or polyclonal antibody specifically binding to GPR101, an antisense nucleic acid, small interfering RNA or chemical analogue of antisense nucleic acid or small interfering RNA specifically hybridizing to GPR101 mRNA, pasireotide, octreotide, lanreotide, a dopamine agonist, and/or a hGHRH peptide antagonist. In such embodiments, the monoclonal or polyclonal antibody is one that specifically recognizes and binds to GPR101, which comprises an amino acid sequence shown in SEQ ID NO: 1, or a fragment thereof. In some particular embodiments, the monoclonal or polyclonal antibody recognizes an epitope (a stretch of 5 or more consecutive amino acid residues within the amino acid sequence). In some embodiments, the antisense nucleic acid or a small interfering RNA is at least 8 nucleotides in length, such as 8 to 1527, or 8 to 500, or 8 to 200, or 8 to 80 nucleotides in length, with some embodiments being 12 to 50, 13 to 40, or 15 to 30 nucleotides in length. And, the antisense nucleic acid or a small interfering RNA specifically hybridises with a nucleic acid molecule encoding GPR101, or specifically hybridises to a nucleic acid having a nucleotide sequence of GPR101, having the nucleotide sequence shown in SEQ ID NO: 2 (or a fragment thereof), and is capable of inhibiting GPR101 expression. In an independent embodiment, the antisense nucleic acid is 100% complementary to the nucleic acid molecule encoding GPR101. Exemplary therapeutic agents that are (i) monoclonal or polyclonal antibodies specifically binding to GPR101, (ii) antisense nucleic acids, (iii) small interfering RNA, (iv) chemical analogues of antisense nucleic acid or small interfering RNA specifically hybridizing to GPR101 mRNA, or (v) hGHRH peptide antagonists are described in U.S. Pat. No.10,350,273, the relevant portion of which is incorporated herein by reference. The compound embodiments and/or pharmaceutical composition embodiments disclosed herein can be administered in the form of solids, liquids, and/or lotions. Suitable solid forms of administration include, but are not limited to, tablets, capsules, powders, solid dispersions, and the like. Suitable liquid or lotion forms include, but are not limited to, oil-in-water or water-in-oil emulsions, aqueous gel compositions, or liquids or lotions formulated for use as foams, films, sprays, ointments, pessary forms, suppository forms, creams, liposomes or in other forms embedded in a matrix for the slow or controlled release of the compound or the pharmaceutical composition to the skin or surface onto which it has been applied or is in contact. In particular disclosed embodiments, a dermal patch can be used to facilitate dosing of the compound or pharmaceutical composition. The compound embodiments and/or pharmaceutical compositions disclosed herein may be formulated so as to be suitable for a variety of modes of administration, including, but not limited to, topical, ocular, oral, buccal, systemic, nasal, injection (such as intravenous, intraperitoneal, subcutaneous, intramuscular, or intrathecal), transdermal (e.g., by mixing with a penetrating agent, such as DMSO), rectal, vaginal, etc., or a form suitable for administration by inhalation or insufflation. For oral or buccal administration, the compound and/or pharmaceutical composition may take the form of lozenges, tablets, or capsules prepared by conventional means with pharmaceutically acceptable excipients. The tablets or capsules may be coated by methods well known in the art with, for example, sugars, films, or enteric coatings. Liquid preparations of the compound and/or pharmaceutical composition for oral administration may take the form of, for example, elixirs, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Preparations for oral administration also may be suitably formulated to give controlled release of the compound or the pharmaceutical composition. For topical administration, the compound and/or the pharmaceutical composition can be formulated as solutions, lotions, gels, ointments, creams, suspensions, etc. For transmucosal administration, penetrants appropriate to the barrier to be permeated can be used. Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration. Useful injectable preparations include sterile suspensions, solutions or emulsions of the compound or pharmaceutical composition in aqueous or oily vehicles. The pharmaceutical composition may also contain formulating agents, such as suspending, stabilizing and/or dispersing agents. For rectal and vaginal routes of administration, the compound and/or pharmaceutical composition may be formulated as solutions (for retention enemas) suppositories or ointments containing conventional suppository bases, such as cocoa butter or other glycerides. For nasal administration or administration by inhalation or insufflation, the compound and/or pharmaceutical composition can be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer with the use of a suitable propellant. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges for use in an inhaler or insufflator (for example capsules and cartridges comprised of gelatin) may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. V. Overview of Several Embodiments Disclosed herein are embodiments of a method comprising exposing a biological sample expressing GPR101 or a subject expressing GPR101 to a compound selected from difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, or any combination thereof; or a stereoisomer, pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof; wherein Formula I is

wherein each of X, X’, and X’’ independently is halogen, NO₂, or haloalkyl; each Y independently is O or CH₂; R is hydrogen or aliphatic; n is an integer selected from 0, 1, or 2; and each of m, m’, and m’’ independently is an integer selected from 0 to 5; and Formula II is

wherein, each of Z, Z’, and Z’’ independently is halogen, NO₂, or haloalkyl; and each of p, p’, and p’’ independently is an integer selected from 0 to 5. In some embodiments, the biological sample is a cell expressing GPR101. In other embodiments, the subject is a human or a non-human animal. In any or all of the above embodiments, the biological sample or the subject is exposed to a therapeutically effective amount of the difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, or any combination thereof; or the stereoisomer, pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof. In any or all of the above embodiments, wherein (i) the difeterol, the vanoxeamine, the compound according to Formula I, the compound according to Formula II, or the combination thereof; or (ii) the stereoisomer, the pharmaceutically acceptable salt, tautomer, the solvate, or the prodrug thereof, is in the form of a pharmaceutical composition further comprising a pharmaceutically acceptable excipient, an adjuvant, an additional therapeutic agent, or any combination thereof. In any or all of the above embodiments, each of X, X’, and X’’ independently is F, Cl, Br, I, NO₂, or CF₃; each Y independently is a bond, O or CH₂; R is hydrogen or lower aliphatic; n is an integer selected from 0, 1, or 2; and each of m, m’, and m’’ independently is an integer selected from 0 or 1; and/or each of Z, Z’, and Z’’ independently is F, Cl, Br, I, NO₂, or CF₃ and each of p, p’, and p’’ independently is 0 or 1. In any or all of the above embodiments, X and X’ is F and each F atom bound at the para position on the ring, and each X’’ is nitro bound at the para position or CF₃ bound at the meta position. In any or all of the above embodiments, each of Z and Z’ is F, if p and p’ are 1; and Z’’ is nitro or CF₃ if p’’ is 1. In any or all of the above embodiments, the compound of Formula I has a structure according to Formula IA, IB, or IC

In any or all of the above embodiments, the compound is selected from difeterol, vanoxeamine, or a compound selected from

Disclosed herein are embodiments of a method, comprising administering to a subject a therapeutically effective amount of a compound selected from difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, or any combination thereof, or a stereoisomer, pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof, to modify hormone production from the hypothalamus and/or the pituitary gland; wherein Formula I is

wherein each of X, X’, and X’’ independently is halogen, NO₂, or haloalkyl; each Y independently is O or CH₂; R is hydrogen or aliphatic; n is an integer selected from 0, 1, or 2; and each of m, m’, and m’’ independently is an integer selected from 0 to 5; and Formula II is

wherein, each of Z, Z’, and Z’’ independently is halogen, NO₂, or haloalkyl; and each of p, p’, and p’’ independently is an integer selected from 0 to 5. In some embodiments, the subject has, or is prone to developing, a disease associated with low levels of growth hormone secretion and exposing the subject to the therapeutically effective amount of the difeterol, the vanoxeamine, the compound according to Formula I, the compound according to Formula II, or the combination thereof, or the stereoisomer, the pharmaceutically acceptable salt, the tautomer, the solvate, or the prodrug thereof, modifies hormone production by increasing the amount of growth hormone secreted from the hypothalamus and/or the pituitary gland. In any or all of the above embodiments, the method increases the subject’s growth velocity. In any or all of the above embodiments, the disease is hypopituitarism, dwarfism, and/or short stature. In any or all of the above embodiments, the low levels of growth hormone secretion include amounts of growth hormone that are below levels of growth hormone secreted by a subject that does not have, or is not prone to developing, the disease. In any or all of the above embodiments, the subject has, or is prone to developing, a disease associated with high levels of growth hormone secretion and exposing the subject to the therapeutically effective amount of the difeterol, the vanoxeamine, the compound according to Formula I, the compound according to Formula II, or the combination thereof, or the stereoisomer, the pharmaceutically acceptable salt, the tautomer, the solvate, or the prodrug thereof, modifies hormone production by decreasing the amount of growth hormone secreted from the hypothalamus and/or the pituitary gland. In any or all of the above embodiments, the disease is acromegaly, gigantism, and/or X-LAG syndrome. In any or all of the above embodiments, the high levels of growth hormone secretion include amounts of growth hormone that are above levels of growth hormone secreted by a subject that does not have, or is not prone to developing, the disease. In any or all of the above embodiments, the subject has an abnormal pituitary gland. In any or all of the above embodiments, the subject has a tumorous pituitary gland, a hyperplastic pituitary gland, or both. In any or all of the above embodiments, the subject is a human. In any or all of the above embodiments, the subject is a non-human animal. In any or all of the above embodiments, the growth hormone secretion is controlled by GPR101. In any or all of the above embodiments, the subject is selected as having a tumorous pituitary gland, a hyperplastic pituitary gland, or both; hypopituitarism; dwarfism; short stature; acromegaly; gigantism; and/or X-LAG syndrome. In any or all of the above embodiments, (i) the difeterol, the vanoxeamine, the compound according to Formula I, the compound according to Formula II, or the combination thereof; or (ii) the stereoisomer, the pharmaceutically acceptable salt, the tautomer, the solvate, or the prodrug thereof is in the form of a pharmaceutical composition further comprising a pharmaceutically acceptable excipient, an adjuvant, an additional therapeutic agent, or any combination thereof. In any or all of the above embodiments, the compound according to Formula I is a compound according to any or all of the above compound embodiments. In any or all of the above embodiments, the compound according to Formula II is a compound according to any or all of the above compound embodiments. Also disclosed herein are embodiments of a method, comprising administering a therapeutically effective amount of difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, or a combination thereof, or a stereoisomer, pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof, to a subject having a pituitary gland tumor to thereby control the growth of the pituitary gland tumor; wherein Formula I is

wherein each of X, X’, and X’’ independently is halogen, NO₂, or haloalkyl; each Y independently is O or CH₂; R is hydrogen or aliphatic; n is an integer selected from 0, 1, or 2; and each of m, m’, and m’’ independently is an integer selected from 0 to 5; and Formula II is

wherein, each of Z, Z’, and Z’’ independently is halogen, NO₂, or haloalkyl; and each of p, p’, and p’’ independently is an integer selected from 0 to 5. Also disclosed are embodiments of a method, comprising: selecting a subject with X-LAG syndrome; and administering to the subject a therapeutically effective amount of difeterol, or a stereoisomer, pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof, or a pharmaceutical composition thereof, thereby reducing growth hormone secretion and treating the X-LAG syndrome in the subject. In some embodiments, the subject has a microduplication in chromosome Xq26.3 comprising the orphan G-protein coupled receptor (GPCR) gene GPR101. In any or all of the above compound embodiments, the subject can be a human. Also disclosed herein are embodiments of a pharmaceutical composition, comprising: difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, or any combination thereof, or a stereoisomer, pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof; and a pharmaceutically acceptable excipient, an adjuvant, an additional therapeutic agent, or any combination thereof; wherein Formula I is

wherein each of X, X’, and X’’ independently is halogen, NO₂, or haloalkyl; each Y independently is O or CH₂; R is hydrogen or aliphatic; n is an integer selected from 0, 1, or 2; and each of m, m’, and m’’ independently is an integer selected from 0 to 5; and Formula II is

wherein, each of Z, Z’, and Z’’ independently is halogen, NO₂, or haloalkyl; and each of p, p’, and p’’ independently is an integer selected from 0 to 5. In some embodiments, the additional therapeutic agent is selected from a monoclonal or polyclonal antibody specifically binding to GPR101, an antisense nucleic acid, small interfering RNA or chemical analogue of antisense nucleic acid or small interfering RNA specifically hybridizing to GPR101 mRNA, pasireotide, octreotide, lanreotide, a dopamine agonist, and/or a hGHRH peptide antagonist. In any or all of the above compound embodiments, the pharmaceutical composition can comprise: difeterol, or a stereoisomer, pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof; a pharmaceutically acceptable excipient; and an additional therapeutic agent selected from a monoclonal or polyclonal antibody specifically binding to GPR101, an antisense nucleic acid, small interfering RNA or chemical analogue of antisense nucleic acid or small interfering RNA specifically hybridizing to GPR101 mRNA, pasireotide, octreotide, lanreotide, a dopamine agonist, and/or a hGHRH peptide antagonist. In any or all of the above compound embodiments, the pharmaceutical composition can be formulated for oral, buccal, sublingual, nasal, pulmonary, or transdermal administration; or subcutaneous, intratumoral, intraperitoneal, intravenous, or intramuscular injection. Also disclosed is a compound for use as a medicament in a method of treatment according to any or all of the above method embodiments. In some embodiments, the method comprises administering to a subject a therapeutically effective amount of the compound to modify hormone production from the hypothalamus and/or the pituitary gland, wherein the compound is selected from difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, or any combination thereof, or a stereoisomer, pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof; wherein Formula I is

wherein each of X, X’, and X’’ independently is halogen, NO₂, or haloalkyl; each Y independently is O or CH₂; R is hydrogen or aliphatic; n is an integer selected from 0, 1, or 2; and each of m, m’, and m’’ independently is an integer selected from 0 to 5; and Formula II is

wherein, each of Z, Z’, and Z’’ independently is halogen, NO₂, or haloalkyl; and each of p, p’, and p’’ independently is an integer selected from 0 to 5. VI. Examples For certain examples described below, each compound is tested in a 6-point intraplate 1:3 titration to generate a detailed concentration-response curve. Hit confirmation is carried out with HEK293AD-GPR101 cells and counter screening with parental HEK293AD cells. Protein kinase inhibitor (PKI, a potent inhibitor of the cAMP pathway) treatment is used as the maximal response for data normalization. Following GPR101 stimulation with the compound for 30 minutes, intracellular cAMP levels are measured using a colorimetric competitive cAMP ELISA kit. And, cAMP-responsive reporter assays are used. In particular examples, HEK293AD-GPR101 cells are transiently transfected with a cAMP responsive element luciferase reporter vector (CRE-Luc) and a control Renilla luciferase vector (R-Luc, for signal normalization) 24 hours before being treated with the compound. Firefly and Renilla luciferase activities are measured consecutively in the same sample using a Dual-Luciferase Reporter Assay System. Example 1 In this example, a biological sample expressing GPR101 was exposed to difeterol. In particular, stable GPR101 HEK293 cells (clone C6) were plated on 121536-well plates at 1000 cells/well. After 24 hours, cells were stimulated with IBMX (500 µM), a PDE inhibitor that promotes cAMP accumulation and thus amplifies the signal. 23 nl/well of difeterol (in DMSO) at 11 different concentrations (1:3 titrations series, concentrations range: 78 nM - 46 µM) was added for 30 minutes. A cAMP HTRF competitive immunoassay was used to measure cAMP accumulation in the cells. Results are illustrated graphically in FIG.1. As can be seen in FIG.1, difeterol showed a complete response curve in the HEK293AD-GPR101 cells, while an inactive curve was observed in control cells. A significant difference between the two curves was seen from 1.7 μM to 46 μM. The IC50 was less than 10 µM and the max response was greater than 80% only in GPR101 cells. It was also determined that the RNA-Seq data for HEK293AD cells did not show upregulation of HRH1, and qPCR (ddPCR analysis) of HEK293 AD-control and stable HEK293 AD- GPR101 cells confirmed there is no expression of HRH1 in either cell line, thus excluding an effect mediated through HRH1. Example 2 In this example, a biological sample expressing GPR101 was exposed to vanoxeamine. In particular, stable GPR101 HEK293 cells (clone C6) were plated on 121536-well plates at 1000 cells/well. After 24 hours, cells were stimulated with IBMX (500 µM), a PDE inhibitor that promotes cAMP accumulation and thus amplifies the signal. 23 nl/well of vanoxeamine (in DMSO) at 11 different concentrations (1:3 titrations series, concentrations range: 78 nM - 46 µM) was added for 30 minutes. A cAMP HTRF competitive immunoassay was used to measure cAMP accumulation in the cells. Results are illustrated graphically in FIG.2. The IC50 was less than greater than µM and the max response was greater than 80% only in GPR101 cells. Example 3 In this example, cytotoxicity of difeterol at different concentrations was assessed. In particular, a cytotoxicity analysis using an ATP content assay was conducted. HEK293 AD-GPR101 cells grown in 100 μL complete medium (DMEM supplemented with 10% FBS) were seeded in 96-well plates (black walls, clear bottom) at a density of 25,000 cells/well in duplicate for each treatment. Two drugs that showed a differential activity in HEK293 AD-GPR101 vs. HEK293 AD cells - difeterol and vanoxeamine - were tested.24 hours after plating, the cells were treated with drugs in a three-fold and five-point serial dilution series from 46 μM to 0.57 μM. After 24 hours of incubation at 37°C in a 5% CO₂ humidified incubator, compound cytotoxicity was analyzed using an adenosine triphosphate (ATP) content assay based on firefly luciferase (ATPLite 1step, PerkinElmer). Briefly, 100 μL of ATP content assay mixture was added to each well. To ensure proper mixing, plates were then shaked at 700 rpm for 2 min in a laboratory orbital microplate shaker. Luminescence values were acquired using a FLUOstar Omega microplate reader (BMG LABTECH). Control wells containing only cells and vehicle [dimethyl sulfoxide (DMSO)] were included on each assay plate. Drug response curve fitting was performed using GraphPad Prism 8 (GraphPad Software, Inc. San Diego, CA). All values are expressed as the mean ± SD. Results from the assay showed that difeterol is cytotoxic only at the highest concentration employed (46 μM). Results from this assay are shown in FIGS.3-6. In another example, cytotoxicity of difeterol in GH3 cells was assessed. Cell counting was conducted using GH3, which is a rat growth hormone (GH)- and prolactin (PRL)-secreting pituitary tumor cell line. These cells are commonly used as a model system for human pituitary tumors secreting GH and PRL. GH3 cells express very little, if any, GPR101. The cells were separately exposed to a vehicle sample and different concentrations of difeterol (0.57 µM, 1.7 µM, 5.1 µM, 15.3 µM, and 46 µM) over a period of 24 hours and 48 hours. As can be seen in FIG.7, the 46 µM dose was observed to be cytotoxic, at least in this example. Example 4 In this example, the effect of difeterol on PRL secretion was assessed. The ALPCO Rat Prolactin ELISA 55-PRLRT-E01 kit was used following manufacturer’s instructions to determine prolactin concentration in the supernatant of GH3 cells treated with difeterol vs. vehicle (DMSO 0.5%). Similar to what was done for the ATP content assay performed in HEK293 AD cells in Example 3, GH3 cells were treated with difeterol in a three-fold and five-point serial dilution series from 46 μM to 0.57 μM. The experiment was performed twice and Data were analyzed using GraphPad Prism 8 (GraphPad Software, Inc. San Diego, CA). All values are expressed as the mean ± SD. Results are shown in FIGS.8 and 9. Example 5 In this example, compound activity is assessed using transgenic cell lines characterized by stable GPR101 expression and high basal cAMP levels. The cells used are HEK-293 AD-GPR101 and a growth hormone (GH) and prolactin-secreting cell line (GH3-GPR101). Following GPR101 stimulation with compound embodiments disclosed herein, the GPR101- mediated response is monitored by evaluating the dynamic changes of cAMP, diacylglycerol (DAG), and calcium. Genetically-encoded fluorescent sensors specific for the cAMP signalling pathway (Green Up cADDis cAMP Assay Kit, #U0200G, Montana Molecular) and DAG signalling (Red Up DAG Assay Kit, #U0300R, Montana Molecular) are used. Both sensors are separately transduced into the transgenic cell lines prior to the stimulation with the compounds to evaluate the dynamic changes of cAMP/DAG. A calcium imaging approach employing a calcium indicator dye (Oregon Green BAPTA-1, O6807, ThermoFisher Scientific) is used to monitor calcium dynamics. All evaluations are performed using an up- to-date imaging system (IX-71 inverted microscope [Olympus] equipped with an electron-multiplying CCD camera [Quantem 512x512, Photometrics] and a light-emitting diode LED [Cairn research, Optoled Lite] as illumination source). This example and the evaluates enable precise functional characterization of GPR101 and quantification of the intracellular effects elicited by compound embodiments of the present disclosure. In addition, inverse agonist compound embodiments are evaluated to determine if they inhibit the production of the pituitary hormones GH and prolactin, which facilitates assessing clinical relevance for the treatment of X-LAG. GH and prolactin production in GH3-GPR101 cells is measured in the supernatants by ELISA (ALPCO kits 22-GHOMS-E01 and 55-PRLRT-E01). Example 6 In this example, compound embodiments of the present disclosure are evaluated for their role in inhibiting GPR101-induced GH secretion that is involved with the Gs and Gq/11 pathways, which involves the activation of Protein kinase A (PKA) and Protein kinase C (PKC). The pituitary adenomas of X-LAG patients, which are characterized by high expression levels of GPR101, have an increase of PKC activity compared to other GH-secreting tumors. Because GPR101 is a constitutively active G-protein-coupled receptor coupled to multiple G proteins that act via Gs- and Gq/11-dependent pathways, the compound embodiments can be effective in treating X-LAG and evaluating their behavior in these pathways is an effective way to determine their applicability in treating such X-LAG and other diseases. In view of the many possible embodiments to which the principles of the present disclosure may be applied, it should be recognized that the illustrated embodiments are only preferred examples and should not be taken as limiting the scope of the disclosure. Rather, the scope is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.

Claims

We claim: 1. A method, comprising exposing a biological sample expressing GPR101 or a subject expressing GPR101 to a compound selected from difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, or any combination thereof; or a stereoisomer, pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof; wherein Formula I is

wherein each of X, X’, and X’’ independently is halogen, NO₂, or haloalkyl; each Y independently is O or CH₂; R is hydrogen or aliphatic; n is an integer selected from 0, 1, or 2; and each of m, m’, and m’’ independently is an integer selected from 0 to 5; and Formula II is

wherein, each of Z, Z’, and Z’’ independently is halogen, NO₂, or haloalkyl; and each of p, p’, and p’’ independently is an integer selected from 0 to 5.

2. The method of claim 1, wherein the biological sample is a cell expressing GPR101.

3. The method of claim 1 or claim 2, wherein the subject is a human or a non-human animal.

4. The method of any one of claims 1-3, wherein the biological sample or the subject is exposed to a therapeutically effective amount of the difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, or any combination thereof; or the stereoisomer, pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof.

5. The method of any one of claims 1-4, wherein (i) the difeterol, the vanoxeamine, the compound according to Formula I, the compound according to Formula II, or the combination thereof; or (ii) the stereoisomer, the pharmaceutically acceptable salt, tautomer, the solvate, or the prodrug thereof, is in the form of a pharmaceutical composition further comprising a pharmaceutically acceptable excipient, an adjuvant, an additional therapeutic agent, or any combination thereof.

6. The method of any one of claims 1-5, wherein each of X, X’, and X’’ independently is F, Cl, Br, I, NO₂, or CF₃; each Y independently is a bond, O or CH₂; R is hydrogen or lower aliphatic; n is an integer selected from 0, 1, or 2; and each of m, m’, and m’’ independently is an integer selected from 0 or 1; and/or each of Z, Z’, and Z’’ independently is F, Cl, Br, I, NO₂, or CF₃ and each of p, p’, and p’’ independently is 0 or 1.

7. The method of any one of claims 1-6, wherein X and X’ is F and each F atom bound at the para position on the ring, and each X’’ is nitro bound at the para position or CF₃ bound at the meta position.

8. The method of any one of claims 1-6, wherein each of Z and Z’ is F, if p and p’ are 1; and Z’’ is nitro or CF₃ if p’’ is 1.

9. The method of any one of claims 1-5, wherein the compound of Formula I has a structure according to Formula IA, IB, or IC

10. The method of any one of claims 1-5, wherein the compound is selected from difeterol, vanoxeamine, or a compound selected from

11. A method, comprising administering to a subject a therapeutically effective amount of a compound selected from difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, or any combination thereof, or a stereoisomer, pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof, to modify hormone production from the hypothalamus and/or the pituitary gland; wherein Formula I is

wherein each of X, X’, and X’’ independently is halogen, NO₂, or haloalkyl; each Y independently is O or CH₂; R is hydrogen or aliphatic; n is an integer selected from 0, 1, or 2; and each of m, m’, and m’’ independently is an integer selected from 0 to 5; and Formula II is

wherein, each of Z, Z’, and Z’’ independently is halogen, NO₂, or haloalkyl; and each of p, p’, and p’’ independently is an integer selected from 0 to 5.

12. The method of claim 11, wherein the subject has, or is prone to developing, a disease associated with low levels of growth hormone secretion and exposing the subject to the therapeutically effective amount of the difeterol, the vanoxeamine, the compound according to Formula I, the compound according to Formula II, or the combination thereof, or the stereoisomer, the pharmaceutically acceptable salt, the tautomer, the solvate, or the prodrug thereof, modifies hormone production by increasing the amount of growth hormone secreted from the hypothalamus and/or the pituitary gland.

13. The method of claim 11 or 12, wherein the method increases the subject’s growth velocity.

14. The method any one of claims 11-13, wherein the disease is hypopituitarism, dwarfism, and/or short stature.

15. The method of claim 12, wherein the low levels of growth hormone secretion include amounts of growth hormone that are below levels of growth hormone secreted by a subject that does not have, or is not prone to developing, the disease.

16. The method of claim 11, wherein the subject has, or is prone to developing, a disease associated with high levels of growth hormone secretion and exposing the subject to the therapeutically effective amount of the difeterol, the vanoxeamine, the compound according to Formula I, the compound according to Formula II, or the combination thereof, or the stereoisomer, the pharmaceutically acceptable salt, the tautomer, the solvate, or the prodrug thereof, modifies hormone production by decreasing the amount of growth hormone secreted from the hypothalamus and/or the pituitary gland.

17. The method of claim 16, wherein the disease is acromegaly, gigantism, and/or X-LAG syndrome.

18. The method of claim 13, wherein the high levels of growth hormone secretion include amounts of growth hormone that are above levels of growth hormone secreted by a subject that does not have, or is not prone to developing, the disease.

19. The method of any one of claims 11-18, wherein the subject has an abnormal pituitary gland.

20. The method of any one of claims 11-19, wherein the subject has a tumorous pituitary gland, a hyperplastic pituitary gland, or both.

21. The method of any one of claims 11-20, wherein the subject is a human.

22. The method of any one of claims 11-20, wherein the subject is a non-human animal.

23. The method of any one of claims 11-22, wherein the growth hormone secretion is controlled by GPR101.

24. The method of any one of claims 11-23, wherein the subject is selected as having a tumorous pituitary gland, a hyperplastic pituitary gland, or both; hypopituitarism; dwarfism; short stature; acromegaly; gigantism; and/or X-LAG syndrome.

25. The method of any one of claims 11-24 wherein (i) the difeterol, the vanoxeamine, the compound according to Formula I, the compound according to Formula II, or the combination thereof; or (ii) the stereoisomer, the pharmaceutically acceptable salt, the tautomer, the solvate, or the prodrug thereof is in the form of a pharmaceutical composition further comprising a pharmaceutically acceptable excipient, an adjuvant, an additional therapeutic agent, or any combination thereof.

26. The method of any one of claims 11-25, wherein the compound according to Formula I is a compound according to any one of claims 6, 7, 9, or 10.

27. The method of any one of claims 11-25, wherein the compound according to Formula II is a compound according to any one of claims 6, 8, or 10.

28. A method, comprising administering a therapeutically effective amount of difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, or a combination thereof, or a stereoisomer, pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof, to a subject having a pituitary gland tumor to thereby control the growth of the pituitary gland tumor; wherein Formula I is

wherein each of X, X’, and X’’ independently is halogen, NO₂, or haloalkyl; each Y independently is O or CH₂; R is hydrogen or aliphatic; n is an integer selected from 0, 1, or 2; and each of m, m’, and m’’ independently is an integer selected from 0 to 5; and Formula II is

wherein, each of Z, Z’, and Z’’ independently is halogen, NO₂, or haloalkyl; and each of p, p’, and p’’ independently is an integer selected from 0 to 5.

29. A method, comprising: selecting a subject with X-LAG syndrome; and administering to the subject a therapeutically effective amount of difeterol, or a stereoisomer, pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof, or a pharmaceutical composition thereof, thereby reducing growth hormone secretion and treating the X-LAG syndrome in the subject.

30. The method of claim 29, wherein the subject has a microduplication in chromosome Xq26.3 comprising the orphan G-protein coupled receptor (GPCR) gene GPR101.

31. The method of claim 29 or claim 30, wherein the subject is a human.

32. A pharmaceutical composition, comprising: difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, or any combination thereof, or a stereoisomer, pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof; and a pharmaceutically acceptable excipient, an adjuvant, an additional therapeutic agent, or any combination thereof; wherein Formula I is

wherein each of X, X’, and X’’ independently is halogen, NO₂, or haloalkyl; each Y independently is O or CH₂; R is hydrogen or aliphatic; n is an integer selected from 0, 1, or 2; and each of m, m’, and m’’ independently is an integer selected from 0 to 5; and Formula II is

wherein, each of Z, Z’, and Z’’ independently is halogen, NO₂, or haloalkyl; and each of p, p’, and p’’ independently is an integer selected from 0 to 5.

33. The pharmaceutical composition of claim 32, wherein the additional therapeutic agent is selected from a monoclonal or polyclonal antibody specifically binding to GPR101, an antisense nucleic acid, small interfering RNA or chemical analogue of antisense nucleic acid or small interfering RNA specifically hybridizing to GPR101 mRNA, pasireotide, octreotide, lanreotide, a dopamine agonist, and/or a hGHRH peptide antagonist.

34. The pharmaceutical composition of claim 32 or claim 33, comprising: difeterol, or a stereoisomer, pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof; a pharmaceutically acceptable excipient; and an additional therapeutic agent selected from a monoclonal or polyclonal antibody specifically binding to GPR101, an antisense nucleic acid, small interfering RNA or chemical analogue of antisense nucleic acid or small interfering RNA specifically hybridizing to GPR101 mRNA, pasireotide, octreotide, lanreotide, a dopamine agonist, and/or a hGHRH peptide antagonist.

35. The pharmaceutical composition of any one of claims 32-34, formulated for oral, buccal, sublingual, nasal, pulmonary, or transdermal administration; or subcutaneous, intratumoral, intraperitoneal, intravenous, or intramuscular injection.

36. A compound for use as a medicament in a method of treatment, the method comprising administering to a subject a therapeutically effective amount of the compound to modify hormone production from the hypothalamus and/or the pituitary gland, wherein the compound is selected from difeterol, vanoxeamine, a compound according to Formula I, a compound according to Formula II, or any combination thereof, or a stereoisomer, pharmaceutically acceptable salt, tautomer, solvate, or prodrug thereof; wherein Formula I is

wherein each of X, X’, and X’’ independently is halogen, NO₂, or haloalkyl; each Y independently is O or CH₂; R is hydrogen or aliphatic; n is an integer selected from 0, 1, or 2; and each of m, m’, and m’’ independently is an integer selected from 0 to 5; and Formula II is

wherein, each of Z, Z’, and Z’’ independently is halogen, NO₂, or haloalkyl; and each of p, p’, and p’’ independently is an integer selected from 0 to 5.