WO2018232225A1 - A dual cb1/gpr18-based signaling system in the murine eye regulates intraocular pressure in a sex-dependent manner - Google Patents

A dual cb1/gpr18-based signaling system in the murine eye regulates intraocular pressure in a sex-dependent manner Download PDF

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WO2018232225A1
WO2018232225A1 PCT/US2018/037727 US2018037727W WO2018232225A1 WO 2018232225 A1 WO2018232225 A1 WO 2018232225A1 US 2018037727 W US2018037727 W US 2018037727W WO 2018232225 A1 WO2018232225 A1 WO 2018232225A1
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activator
gpr18
targeting
receptor
dual
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Alex STRAIKER
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Indiana University Research And Technology Corporation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears

Definitions

  • the field of the disclosure relates generally to dual activation of cannabinoid receptor type 1 (CBl) and G-protein coupled receptor 18 (GPR18) receptors to reduce intraocular pressure (IOP) in the mammalian eye. More particularly, activation of this dual CBl/GPR18-based signaling system has been found to reduce intraocular pressure (IOP) in male mammalian eyes, providing a potential treatment for glaucoma.
  • CBl cannabinoid receptor type 1
  • GPR18 G-protein coupled receptor 18
  • a 9 -tetrahydrocannabinol (A 9 -THC) lower intraocular pressure (IOP). Elevated IOP remains the chief hallmark and therapeutic target for glaucoma, a condition that places millions at risk of blindness.
  • a 9 -THC as a potential tool for lowering IOP, it is still unknown how A 9 -THC regulates IOP.
  • a 9 -THC pharmacology is that ⁇ 9 - THC is not a very 'good' agonist of CB1 receptors. More particularly, A 9 -THC has shown high affinity, low efficacy at CB1 receptors, and thus, could serve as a functional antagonist. One would expect a more efficacious agonist, such as WIN55212 or CP55940, to be better suited to the task.
  • a 9 -THC is also not a particularly 'clean' drug - it is widely appreciated that A 9 -THC activates not only the canonical cannabinoid receptors, but other related receptors, and further, may have other off- target actions. This combination of poor efficacy and non-selectivity is often the kiss of death for a potential therapeutic agent.
  • Elevated IOP is implicated in most forms of glaucoma, a disease responsible for millions of cases of blindness worldwide. Treatments for glaucoma exist, but not for all forms, and often with side-effects. Specifically, though there are five classes of drugs currently approved for therapeutic use in the treatment of glaucoma via IOP reduction, there remain incidences of patients who are unresponsive to these medications, or who develop tolerance to existing treatments.
  • the present disclosure is generally directed to methods of activating a dual CBl/GPR18-based signaling system in the eye to lower intraocular pressure (IOP) in a sex-dependent manner.
  • IOP intraocular pressure
  • both CB1 and GPR18 are receptors that have been detected in the eyes of mammals. It has now been found that dual activation of these receptors, such as with activators like THC, lowers intraocular pressure substantially, particularly in males, thereby providing potential as a treatment to glaucoma.
  • the present disclosure is directed to a method for activating a dual CBl/GPR18-based signaling system in the eye of a subject in need thereof.
  • the method comprises administering to the subject at least one activator for targeting a CB 1 receptor in the eye and at least one activator for targeting a GPR18 receptor in the eye.
  • the present disclosure is directed to a method for reducing intraocular pressure in a subject in need thereof. The method comprises administering to the subject at least one activator for targeting a CB1 receptor in the eye and at least one activator for targeting a GPR18 receptor in the eye.
  • the present disclosure is directed to a method for treating glaucoma in a subject in need thereof.
  • the method comprises administering to the subject at least one activator for targeting a CB1 receptor in the eye and at least one activator for targeting a GPR18 receptor in the eye.
  • FIGS. 1A & IB depict the effect of A 9 -THC on lowering IOP as analyzed in Example 1. As shown, A 9 -THC lowered IOP for 8 hours in male mice, but in female mice no significant reduction was seen at 1 hour and the reduction at 4 hours was less than that seen in males.
  • FIG. 1A Male mice tested at various times post- THC treatment saw declines in IOP at 1, 4 and 8 hours.
  • FIG. IB In contrast, female mice saw no decline at 1 hour, but did at 4 hours, though to a lesser extent than males.
  • FIGS. 2A & 2B depict the dual action of A 9 -THC on CB1 and GPR18 receptors.
  • a 9 -THC lowered IOP via a combination of CB1 and GPR18 receptors.
  • CB1 deletion prevented the A 9 -THC reduction of IOP at 4 hours (FIG. 2B), but reduction remained intact at 1 hour (FIG. 2A), indicating that A 9 -THC was still lowering IOP via a second target.
  • FIGS. 3 A & 3B depict the dual action of A 9 -THC on CB1 and GPR18 receptors.
  • a 9 -THC lowered IOP via a combination of CB1 and GPR18 receptors.
  • Pretreatment with GPR18 antagonist 01918 (5 mM) prevents the drop in IOP by A 9 -THC, indicating that this inhibition occurs via dual activation of CB1 and GPR18 receptors.
  • the present disclosure is generally directed to methods of activating a dual CBl/GPR18-based signaling system in the eye. Upon activation, it has been found that this signaling system can lower intraocular pressure (IOP) in a sex- dependent manner, such to provide a potential treatment for glaucoma in male subjects in need thereof.
  • the signaling system may be activated by the dual agonist, A 9 -tetrahydrocannabinol (A 9 -THC), that targets both the CBl receptor and the GPR18 receptor in the eyes of the subject.
  • target refers to the agonist and/or synthetic ligand (referred to collectively as “activator") binding to at least one of the CBl and/or GPR18 receptors via a receptor-ligand interaction.
  • activators described herein dually target the CBl and/or GPR18 receptors, thereby activating a dual CBl/GPR18-based signaling system.
  • IOP intraocular pressure
  • the activators for targeting the CBl and GPR18 receptors include both agonists/ligands having a dual mode of targeting the receptors, such as the dual activator, A 9 -tetrahydrocannabinol ((-)-(6aR,10aR)-6,6,9-Trimethyl-3-pentyl- 6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-l-ol (A 9 -THC)), as well as activators that in combination target one or the other of the CBl and/or GPR18 receptors.
  • a 9 -tetrahydrocannabinol ((-)-(6aR,10aR)-6,6,9-Trimethyl-3-pentyl- 6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-l-ol (A 9 -THC)
  • monoacylglyerol lipase (MAGL) blockers e.g., 2-arachidonoyl glycerol (2- AG) (l,3-Dihydroxy-2-propanyl (5Z,8Z,11Z,14Z)- 5,8,11,14-eicosatetraenoate)
  • 2-arachidonoyl glycerol (2- AG) l,3-Dihydroxy-2-propanyl (5Z,8Z,11Z,14Z)- 5,8,11,14-eicosatetraenoate
  • 2-[(lR,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol (CP55940) activate CBl, while N- arachidonoylglycine (NAGly) ((5Z,8Z,l lZ,14Z)-N-Icosa-5,8,ll,14-tetraenoylamin
  • the dual targeting activator(s) can be administered to a subject in need thereof to activate a
  • subject in need thereof refers to a subset of subjects in need of controlling/minimizing/reducing IOP.
  • Some subjects that are in specific need of controlled/minimized/reduced IOP may include subjects who are susceptible to, or at elevated risk of, experiencing symptoms of glaucoma.
  • Subjects may be susceptible to, or at elevated risk of, experiencing symptoms of glaucoma due to family history, age, environment, and/or lifestyle.
  • the dual activators can be administered to male subjects in need thereof.
  • the CB1/GPR18 activator(s) is administered in an amount such to provide an effective amount of the activator to the subject.
  • the effective amount is that which may treat or alleviate the disease or symptoms of the disease at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the total daily usage of the activators described herein may be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular subject will depend upon a variety of factors, including the condition, disease or disorder being treated and the severity of the condition, disease or disorder; activity of the specific activator(s) employed; the age, body weight, general health, gender and diet of the patient: the time of administration, route of administration, and rate of excretion of the specific activator(s) employed; the duration of the treatment; drugs used in combination or coincidentally with the specific activator(s) employed; and like factors well known to the researcher, veterinarian, medical doctor or other clinician of ordinary skill.
  • the effective amount is advantageously selected with reference to any toxicity, or other undesirable side effect, that might occur during administration of one or more of the activators described herein.
  • the co-therapies described herein may allow for the administration of lower doses of activators that show such toxicity, or other undesirable side effect, where those lower doses are below thresholds of toxicity or lower in the therapeutic window than would otherwise be administered in the absence of a co-therapy.
  • the dual CB1/GPR18- based signaling system may be activated by one or more activators, and, for topical ocular application, the activator(s) is administered to the subject in amounts ranging from about 1 mM to about 20 mM, depending on the properties of the activator administered.
  • the dual activator is THC, and is administered to the subject in an amount of from about 1 mM to about 10 mM, and including about 5 mM.
  • administering refers chiefly to topical ocular application, but also includes all means of introducing the activators described herein to the subject, including, but not limited to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal, and the like.
  • the activators described herein may be administered in unit dosage forms and/or formulations containing conventional nontoxic pharmaceutically-acceptable carriers, adjuvants, and vehicles.
  • an effective amount of one or more activator in any of the various forms described herein may be mixed with one or more excipients, diluted by one or more excipients, or enclosed within such a carrier which can be in the form of a capsule, sachet, paper, or other container.
  • Excipients may serve as a diluent, and can be solid, semi-solid, or liquid materials, which act as a vehicle, carrier or medium for the active ingredient.
  • the activator is administered with the use of TOCRISOLVETM (Tocris Bioscience), a soya based vehicle that allows for improved corneal transit and bioavailability.
  • the CB1/GPR18 activator(s) can be administered in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the CB1/GPR18 activator-containing formulations may contain anywhere from about 0.1% to about 99.9% active ingredients, depending upon the selected dose and dosage form.
  • the present invention provides a method for activating a dual CBl/GPR18-based signaling system in the eye of a subject in need thereof, the method comprising administering to the subject at least one activator for targeting a CB1 receptor in the eye and at least one activator for targeting a GPR18 receptor in the eye.
  • the activator for targeting the GPR18 receptor is selected from the group consisting of N- arachidonoylglycine (NAGly), abnormal cannabidiol (abnCBD), 5-methyl-4-[(lR,6R)- 3-methyl-6-prop-l-en-2-ylcyclohex-2-en-l-yl]benzene-l,3-diol (O1602), 1,3- dimethoxy-5 -methyl-2- [( lR,6R)-3-methyl-6-prop- 1 -en-2-ylcyclohex-2-en- 1 -yl]benzene (01918) and combinations thereof.
  • the subject is a male mammal.
  • a method for reducing intraocular pressure in a subject in need thereof comprising administering to the subject at least one activator for targeting a CBl receptor in the eye and at least one activator for targeting a GPR18 receptor in the eye.
  • the activator targeting the GPR18 receptor is selected from the group consisting of N- arachidonoylglycine (NAGly), abnormal cannabidiol (abnCBD), 5-methyl-4-[(lR,6R)- 3-methyl-6-prop-l-en-2-ylcyclohex-2-en-l-yl]benzene-l,3-diol (O1602), 1,3- dimethoxy-5 -methyl-2- [( lR,6R)-3-methyl-6-prop- 1 -en-2-ylcyclohex-2-en- 1 -yl]benzene (01918) and combinations thereof.
  • NAGly N- arachidonoylglycine
  • abnCBD abnormal cannabidiol
  • a method for treating glaucoma in a subject in need thereof comprising administering to the subject at least one activator for targeting a CBl receptor in the eye and at least one activator for targeting a GPR18 receptor in the eye.
  • the activator targeting the GPR18 receptor is selected from the group consisting of N- arachidonoylglycine (NAGly), abnormal cannabidiol (abnCBD), 5-methyl-4-[(lR,6R)- 3-methyl-6-prop-l-en-2-ylcyclohex-2-en-l-yl]benzene-l,3-diol (O1602), 1,3- dimethoxy-5 -methyl-2- [( lR,6R)-3-methyl-6-prop- 1 -en-2-ylcyclohex-2-en- 1 -yl]benzene (01918) and combinations thereof.
  • NAGly N- arachidonoylglycine
  • abnCBD abnormal cannabidiol
  • IOP is measured in mice by rebound tonometry, using a Tonolab (Icare Finland Oy, Helsinki, Finland). This instrument uses a light plastic- tipped probe to briefly make contact with the cornea; after the probe encounters the eye, the instrument measures the speed at which the probe rebounds in order to calculate IOP.
  • mice were anesthetized with isoflurane (3% induction). The anesthetized mouse was then placed on a platform in a prone position, where anesthesia was maintained with 2% isoflurane through a nose-cone. Baseline IOP measurements were taken in both eyes. A "measurement” consists of the average value of six readings. One eye was then treated with drug (dissolved in Tocrisolve (Tocris Biosciences), a soya-based solvent, 5 ⁇ . final volume applied topically), while the other eye was treated with vehicle. The animal was then allowed to recover. After an hour, the animal was again anesthetized as above. IOP was then measured in the drug-treated and vehicle-treated contralateral eye. In principle, anesthesia may alter IOP, however tests of IOP in contralateral eyes of the same animal means that observed effects are independent of hypothesized anesthetic effects on IOP.
  • IOP measurements following drug administration were analyzed by unpaired t-tests comparing drug-treated eyes to vehicle-treated eyes.
  • Tetrahydrocannabinol (A 9 -THC) was obtained from the National Institute on Drug Abuse (NIDA) drug supply program.
  • a 9 -THC preferentially reduces pressure in male mice
  • mice treated with THC did not see a significant drop in IOP at 1 hour and a more modest effect amounting to a 12% drop at 4 hours (FIG. IB).
  • a 9 -THC lowers IOP via a combination of CB1 and GPR18 receptors.
  • a 9 -THC lowers IOP. It has been previously shown that CB 1 receptor activation lowers IOP (and that activating CB2 receptors does not). It is therefore likely that at least part of the effect of A 9 -THC is via activation of CB1 receptors. Moreover, if the effects of ⁇ 9 - THC are mediated entirely by CB1 receptors, then A 9 -THC should have no effect on IOP in CB1 knockout mice. Interestingly, it was found, however, that A 9 -THC still lowered IOP, though to a lesser extent, in CB1 knockout mice. At 1 hour, A 9 -THC still significantly lowered IOP, though by four hours, there was no longer a statistically significant drop (FIGS. 2A & 2B).
  • CBl/GPR18-based signaling system in the mammalian eye lowers IOP. It does so selectively in males of the species tested. Because glaucoma remains a major cause of blindness, with a substantial number of patients unresponsive to conventional treatments, the identification of a novel mechanism to lower IOP is therefore of great therapeutic interest. These results suggest that CB1/GPR18 may serve as a desirable dual target for development of novel ocular hypotensive medications.

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Abstract

Methods of activating a dual CB1/GPR18-based signaling system in the mammalian eye are disclosed. More particularly, activation of the dual CB1/GPR18-based signaling system has been found to reduce intraocular pressure (IOP) in male mammalian eyes, providing a potential treatment for glaucoma.

Description

A DUAL CB 1/GPRl 8-B ASED SIGNALING SYSTEM IN THE MURINE EYE REGULATES INTRAOCULAR PRESSURE IN A SEX-DEPENDENT MANNER
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH & DEVELOPMENT
[0001] This invention was made with government support under EY024625 awarded by the National Institutes of Health. The Government has certain rights in the invention.
CROSS REFERENCE TO RELATED APPLICATIONS
[0002] This application claims priority to U.S. Provisional Patent Application Serial No. 62/520,987, filed on June 16, 2017, the disclosure of which is incorporated by reference herein in its entirety.
BACKGROUND OF THE DISCLOSURE
[0003] The field of the disclosure relates generally to dual activation of cannabinoid receptor type 1 (CBl) and G-protein coupled receptor 18 (GPR18) receptors to reduce intraocular pressure (IOP) in the mammalian eye. More particularly, activation of this dual CBl/GPR18-based signaling system has been found to reduce intraocular pressure (IOP) in male mammalian eyes, providing a potential treatment for glaucoma.
[0004] It has been known for nearly 50 years that marijuana and its chief psychoactive component A9-tetrahydrocannabinol (THC) (A9-THC) lower intraocular pressure (IOP). Elevated IOP remains the chief hallmark and therapeutic target for glaucoma, a condition that places millions at risk of blindness. Despite considerable early interest in (and continued public perception of) A9-THC as a potential tool for lowering IOP, it is still unknown how A9-THC regulates IOP.
[0005] Some efforts were made to determine the mechanism of action using pharmacological approaches. Given that A9-THC is known to activate CBl receptors, and that both A9-THC and CBl activation result in lowered IOP, it was reasonable to surmise that A9-THC lowers IOP via activation of CBl. However, this has never been convincingly determined to be the case. Indeed the picture appears to be more complex for several reasons. Particularly, based on its pharmacological profile, one would not consider A9-THC an ideal candidate molecule for regulation of IOP. One curious, and widely under-appreciated, aspect of A9-THC pharmacology is that Δ9- THC is not a very 'good' agonist of CB1 receptors. More particularly, A9-THC has shown high affinity, low efficacy at CB1 receptors, and thus, could serve as a functional antagonist. One would expect a more efficacious agonist, such as WIN55212 or CP55940, to be better suited to the task. A9-THC is also not a particularly 'clean' drug - it is widely appreciated that A9-THC activates not only the canonical cannabinoid receptors, but other related receptors, and further, may have other off- target actions. This combination of poor efficacy and non-selectivity is often the kiss of death for a potential therapeutic agent.
[0006] Elevated IOP is implicated in most forms of glaucoma, a disease responsible for millions of cases of blindness worldwide. Treatments for glaucoma exist, but not for all forms, and often with side-effects. Specifically, though there are five classes of drugs currently approved for therapeutic use in the treatment of glaucoma via IOP reduction, there remain incidences of patients who are unresponsive to these medications, or who develop tolerance to existing treatments.
[0007] Accordingly, there is a continuing need for new treatments for reducing IOP, and treating glaucoma.
BRIEF DESCRIPTION OF THE DISCLOSURE
[0008] The present disclosure is generally directed to methods of activating a dual CBl/GPR18-based signaling system in the eye to lower intraocular pressure (IOP) in a sex-dependent manner. More particularly, both CB1 and GPR18 are receptors that have been detected in the eyes of mammals. It has now been found that dual activation of these receptors, such as with activators like THC, lowers intraocular pressure substantially, particularly in males, thereby providing potential as a treatment to glaucoma.
[0009] Accordingly, in one embodiment, the present disclosure is directed to a method for activating a dual CBl/GPR18-based signaling system in the eye of a subject in need thereof. The method comprises administering to the subject at least one activator for targeting a CB 1 receptor in the eye and at least one activator for targeting a GPR18 receptor in the eye. [0010] In another embodiment, the present disclosure is directed to a method for reducing intraocular pressure in a subject in need thereof. The method comprises administering to the subject at least one activator for targeting a CB1 receptor in the eye and at least one activator for targeting a GPR18 receptor in the eye.
[0011] In yet another embodiment, the present disclosure is directed to a method for treating glaucoma in a subject in need thereof. The method comprises administering to the subject at least one activator for targeting a CB1 receptor in the eye and at least one activator for targeting a GPR18 receptor in the eye.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIGS. 1A & IB depict the effect of A9-THC on lowering IOP as analyzed in Example 1. As shown, A9-THC lowered IOP for 8 hours in male mice, but in female mice no significant reduction was seen at 1 hour and the reduction at 4 hours was less than that seen in males. FIG. 1A: Male mice tested at various times post- THC treatment saw declines in IOP at 1, 4 and 8 hours. FIG. IB: In contrast, female mice saw no decline at 1 hour, but did at 4 hours, though to a lesser extent than males.
[0013] FIGS. 2A & 2B depict the dual action of A9-THC on CB1 and GPR18 receptors. A9-THC lowered IOP via a combination of CB1 and GPR18 receptors. CB1 deletion prevented the A9-THC reduction of IOP at 4 hours (FIG. 2B), but reduction remained intact at 1 hour (FIG. 2A), indicating that A9-THC was still lowering IOP via a second target.
[0014] FIGS. 3 A & 3B depict the dual action of A9-THC on CB1 and GPR18 receptors. A9-THC lowered IOP via a combination of CB1 and GPR18 receptors. Pretreatment with GPR18 antagonist 01918 (5 mM) prevents the drop in IOP by A9-THC, indicating that this inhibition occurs via dual activation of CB1 and GPR18 receptors.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0015] The present disclosure is generally directed to methods of activating a dual CBl/GPR18-based signaling system in the eye. Upon activation, it has been found that this signaling system can lower intraocular pressure (IOP) in a sex- dependent manner, such to provide a potential treatment for glaucoma in male subjects in need thereof. In some embodiments, the signaling system may be activated by the dual agonist, A9-tetrahydrocannabinol (A9-THC), that targets both the CBl receptor and the GPR18 receptor in the eyes of the subject.
[0016] As used herein, "target", "targeting", and the like refer to the agonist and/or synthetic ligand (referred to collectively as "activator") binding to at least one of the CBl and/or GPR18 receptors via a receptor-ligand interaction. The activators described herein dually target the CBl and/or GPR18 receptors, thereby activating a dual CBl/GPR18-based signaling system.
[0017] It has surprisingly been found upon activation of the dual CBl/GPR18-based signaling system by activators, intraocular pressure (IOP) can be reduced in a sex-dependent manner.
ACTIVATION OF THE DUAL CB1/GPR18-BASED SIGNALING
SYSTEM
[0018] The activators for targeting the CBl and GPR18 receptors include both agonists/ligands having a dual mode of targeting the receptors, such as the dual activator, A9-tetrahydrocannabinol ((-)-(6aR,10aR)-6,6,9-Trimethyl-3-pentyl- 6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-l-ol (A9-THC)), as well as activators that in combination target one or the other of the CBl and/or GPR18 receptors.
[0019] For example, monoacylglyerol lipase (MAGL) blockers (e.g., 2-arachidonoyl glycerol (2- AG) (l,3-Dihydroxy-2-propanyl (5Z,8Z,11Z,14Z)- 5,8,11,14-eicosatetraenoate)) and/or 2-[(lR,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol (CP55940) activate CBl, while N- arachidonoylglycine (NAGly) ((5Z,8Z,l lZ,14Z)-N-Icosa-5,8,ll,14-tetraenoylamino- acetic acid), abnormal cannabidiol (abnCBD) (4-[(lR,6R)-3-methyl-6-prop-l-en-2- ylcyclohex-2-en-l-yl]-5-pentylbenzene-l,3-diol), 5-methyl-4-[(lR,6R)-3-methyl-6- prop-l-en-2-ylcyclohex-2-en-l-yl]benzene-l,3-diol (O1602) and/or l,3-dimethoxy-5- methyl-2- [( 1 R,6R)-3 -methyl-6-prop- 1 -en-2-ylcyclohex-2-en- 1 -yl]benzene (01918) activate GPR18. Any one or more of the CBl activators could be administered with any one or more GPR18 as a combination therapy to target both receptors.
[0020] As noted above, it has been surprisingly found that the dual targeting activator(s) can be administered to a subject in need thereof to activate a
CBl/GPR18-based signaling system in the eye, thereby lowing intraocular pressure (IOP), and providing a treatment for glaucoma. As used herein, "subject in need thereof refers to a subset of subjects in need of controlling/minimizing/reducing IOP. Some subjects that are in specific need of controlled/minimized/reduced IOP, may include subjects who are susceptible to, or at elevated risk of, experiencing symptoms of glaucoma. Subjects may be susceptible to, or at elevated risk of, experiencing symptoms of glaucoma due to family history, age, environment, and/or lifestyle. Based on the foregoing, because some of the method embodiments of the present disclosure are directed to specific subsets or subclasses of identified subjects (that is, the subset or subclass of subjects "in need" of assistance in addressing one or more specific conditions noted herein), not all subjects will fall within the subset or subclass of subjects as described herein for certain diseases, disorders or conditions.
[0021] In particularly suitable embodiments, it has been found that the dual activators can be administered to male subjects in need thereof.
[0022] Typically, the CB1/GPR18 activator(s) is administered in an amount such to provide an effective amount of the activator to the subject. The term "effective amount" as used herein, refers to that amount of active compound (i.e., CB1 and/or GPR18 activator) or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the condition, disease or disorder being treated. In one aspect, the effective amount is that which may treat or alleviate the disease or symptoms of the disease at a reasonable benefit/risk ratio applicable to any medical treatment. However, it is to be understood that the total daily usage of the activators described herein may be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject will depend upon a variety of factors, including the condition, disease or disorder being treated and the severity of the condition, disease or disorder; activity of the specific activator(s) employed; the age, body weight, general health, gender and diet of the patient: the time of administration, route of administration, and rate of excretion of the specific activator(s) employed; the duration of the treatment; drugs used in combination or coincidentally with the specific activator(s) employed; and like factors well known to the researcher, veterinarian, medical doctor or other clinician of ordinary skill. [0023] It is also appreciated that the effective amount, whether referring to monotherapy or combination therapy, is advantageously selected with reference to any toxicity, or other undesirable side effect, that might occur during administration of one or more of the activators described herein. Further, it is appreciated that the co-therapies described herein may allow for the administration of lower doses of activators that show such toxicity, or other undesirable side effect, where those lower doses are below thresholds of toxicity or lower in the therapeutic window than would otherwise be administered in the absence of a co-therapy.
[0024] In particularly suitable embodiments, the dual CB1/GPR18- based signaling system may be activated by one or more activators, and, for topical ocular application, the activator(s) is administered to the subject in amounts ranging from about 1 mM to about 20 mM, depending on the properties of the activator administered. For example, in one embodiment, the dual activator is THC, and is administered to the subject in an amount of from about 1 mM to about 10 mM, and including about 5 mM.
[0025] The term "administering" as used herein refers chiefly to topical ocular application, but also includes all means of introducing the activators described herein to the subject, including, but not limited to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal, and the like. The activators described herein may be administered in unit dosage forms and/or formulations containing conventional nontoxic pharmaceutically-acceptable carriers, adjuvants, and vehicles.
[0026] In some embodiments, an effective amount of one or more activator in any of the various forms described herein may be mixed with one or more excipients, diluted by one or more excipients, or enclosed within such a carrier which can be in the form of a capsule, sachet, paper, or other container. Excipients may serve as a diluent, and can be solid, semi-solid, or liquid materials, which act as a vehicle, carrier or medium for the active ingredient. In one embodiment, the activator is administered with the use of TOCRISOLVE™ (Tocris Bioscience), a soya based vehicle that allows for improved corneal transit and bioavailability.
[0027] Thus, the CB1/GPR18 activator(s) can be administered in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. The CB1/GPR18 activator-containing formulations may contain anywhere from about 0.1% to about 99.9% active ingredients, depending upon the selected dose and dosage form.
[0028] The following paragraphs enumerated consecutively from 1 through 23 provide for various aspects of the present invention. In one embodiment, in a first paragraph (1), the present invention provides a method for activating a dual CBl/GPR18-based signaling system in the eye of a subject in need thereof, the method comprising administering to the subject at least one activator for targeting a CB1 receptor in the eye and at least one activator for targeting a GPR18 receptor in the eye.
[0029] 2. The method of paragraph 1, wherein the least one activator for targeting the CB1 receptor and at least one activator for targeting the GPR18 receptor are the same activator, functioning as a dual activator.
[0030] 3. The method of paragraph 2, wherein the dual activator is administered topically to the eye.
[0031] 4. The method of either paragraph 2 or 3, wherein the dual activator is A9-tetrahydrocannabinol (A9-THC).
[0032] 5. The method of paragraph 4, wherein Δ9- tetrahydrocannabinol (A9-THC) is administered topically to the eye in an amount ranging from about 1 mM to about 20 mM.
[0033] 6. The method of paragraph 1 comprising administering to the subject a monoacylglyerol lipase (MAGL) blocker as the activator for targeting the CB1 receptor in combination with the activator for targeting the GPR18 receptor.
[0034] 7. The method of paragraph 6, wherein the activator for targeting the GPR18 receptor is selected from the group consisting of N- arachidonoylglycine (NAGly), abnormal cannabidiol (abnCBD), 5-methyl-4-[(lR,6R)- 3-methyl-6-prop-l-en-2-ylcyclohex-2-en-l-yl]benzene-l,3-diol (O1602), 1,3- dimethoxy-5 -methyl-2- [( lR,6R)-3-methyl-6-prop- 1 -en-2-ylcyclohex-2-en- 1 -yl]benzene (01918) and combinations thereof. [0035] 8. The method of any of paragraphs 1 through 7, wherein the subject is a male mammal.
[0036] 9. A method for reducing intraocular pressure in a subject in need thereof, the method comprising administering to the subject at least one activator for targeting a CBl receptor in the eye and at least one activator for targeting a GPR18 receptor in the eye.
[0037] 10. The method of paragraph 9, wherein the least one activator for targeting the CBl receptor and at least one activator for targeting the GPR18 receptor are the same activator, functioning as a dual activator
[0038] 11. The method of paragraph 10, wherein the dual activator is administered topically to the eye.
[0039] 12. The method of either paragraph 10 or 11, wherein the dual activator is A9-tetrahydrocannabinol (A9-THC).
[0040] 13. The method of paragraph 12, wherein Δ9- tetrahydrocannabinol (A9-THC) is administered topically to the eye in an amount ranging from about 1 mM to about 20 mM.
[0041] 14. The method of paragraph 9 comprising administering to the subject a monoacylglyerol lipase (MAGL) blocker in combination with the activator targeting the GPR18 receptor.
[0042] 15. The method of paragraph 14, wherein the activator targeting the GPR18 receptor is selected from the group consisting of N- arachidonoylglycine (NAGly), abnormal cannabidiol (abnCBD), 5-methyl-4-[(lR,6R)- 3-methyl-6-prop-l-en-2-ylcyclohex-2-en-l-yl]benzene-l,3-diol (O1602), 1,3- dimethoxy-5 -methyl-2- [( lR,6R)-3-methyl-6-prop- 1 -en-2-ylcyclohex-2-en- 1 -yl]benzene (01918) and combinations thereof.
[0043] 16. The method of any of paragraphs 9 through 15, wherein the subject is a male mammal. [0044] 17. A method for treating glaucoma in a subject in need thereof, the method comprising administering to the subject at least one activator for targeting a CBl receptor in the eye and at least one activator for targeting a GPR18 receptor in the eye.
[0045] 18. The method of paragraph 17, wherein the least one activator for targeting the CBl receptor and at least one activator for targeting the GPR18 receptor are the same activator, functioning as a dual activator.
[0046] 19. The method of paragraph 18, wherein the dual activator is administered topically to the eye.
[0047] 20. The method of either paragraph 17 or 18, wherein the dual activator is administered topically to the eye in an amount ranging from about 1 mM to about 20 mM.
[0048] 21. The method of paragraph 17 comprising administering to the subject a monoacylglyerol lipase (MAGL) blocker in combination with the activator targeting the GPR18 receptor.
[0049] 22. The method of paragraph 21, wherein the activator targeting the GPR18 receptor is selected from the group consisting of N- arachidonoylglycine (NAGly), abnormal cannabidiol (abnCBD), 5-methyl-4-[(lR,6R)- 3-methyl-6-prop-l-en-2-ylcyclohex-2-en-l-yl]benzene-l,3-diol (O1602), 1,3- dimethoxy-5 -methyl-2- [( lR,6R)-3-methyl-6-prop- 1 -en-2-ylcyclohex-2-en- 1 -yl]benzene (01918) and combinations thereof.
[0050] 23. The method of any of paragraphs 17 through 22, wherein the subject is a male mammal.
[0051] The following examples further illustrate specific embodiments of the present disclosure; however, the following illustrative examples should not be interpreted in any way to limit the disclosure.
EXAMPLE
[0052] In this Example, potential therapeutic effects of a dual activating target of CBl and GPR18 was evaluated. MATERIALS AND METHODS
[0053] IOP is measured in mice by rebound tonometry, using a Tonolab (Icare Finland Oy, Helsinki, Finland). This instrument uses a light plastic- tipped probe to briefly make contact with the cornea; after the probe encounters the eye, the instrument measures the speed at which the probe rebounds in order to calculate IOP.
[0054] To obtain reproducible IOP measurements, mice were anesthetized with isoflurane (3% induction). The anesthetized mouse was then placed on a platform in a prone position, where anesthesia was maintained with 2% isoflurane through a nose-cone. Baseline IOP measurements were taken in both eyes. A "measurement" consists of the average value of six readings. One eye was then treated with drug (dissolved in Tocrisolve (Tocris Biosciences), a soya-based solvent, 5 μΐ. final volume applied topically), while the other eye was treated with vehicle. The animal was then allowed to recover. After an hour, the animal was again anesthetized as above. IOP was then measured in the drug-treated and vehicle-treated contralateral eye. In principle, anesthesia may alter IOP, however tests of IOP in contralateral eyes of the same animal means that observed effects are independent of hypothesized anesthetic effects on IOP.
[0055] IOP measurements following drug administration were analyzed by unpaired t-tests comparing drug-treated eyes to vehicle-treated eyes.
Drugs
[0056] Tetrahydrocannabinol (A9-THC) was obtained from the National Institute on Drug Abuse (NIDA) drug supply program.
RESULTS
A9-THC preferentially reduces pressure in male mice
[0057] The effect of 5mM topical A9-THC in a normotensive murine model of IOP was analyzed. The advantage of this model is that it allows the use of transgenic mice such as CB1 knockouts. Moreover these mice exhibit a strong cannabinoid-receptor dependent reduction in IOP, approaching 30%. The effect of THC-treated eyes was tested relative to contralateral vehicle-treated eyes at 1, 4, 8 and 12 hours post-treatment. It was found that THC lowered IOP as expected with a robust inhibition even at 8 hours, that was absent by 12 hours (FIG. 1A). Strikingly, the peak inhibition at 8 hours was a substantial 28% drop from baseline.
[0058] Even more strikingly, however, is that these effects were very different in female mice. Female mice treated with THC did not see a significant drop in IOP at 1 hour and a more modest effect amounting to a 12% drop at 4 hours (FIG. IB).
A9-THC lowers IOP via a combination of CB1 and GPR18 receptors.
[0059] As noted above, it was previously unclear how exactly A9-THC lowers IOP. It has been previously shown that CB 1 receptor activation lowers IOP (and that activating CB2 receptors does not). It is therefore likely that at least part of the effect of A9-THC is via activation of CB1 receptors. Moreover, if the effects of Δ9- THC are mediated entirely by CB1 receptors, then A9-THC should have no effect on IOP in CB1 knockout mice. Interestingly, it was found, however, that A9-THC still lowered IOP, though to a lesser extent, in CB1 knockout mice. At 1 hour, A9-THC still significantly lowered IOP, though by four hours, there was no longer a statistically significant drop (FIGS. 2A & 2B).
DISCUSSION
[0060] The most significant findings were 1) that A9-THC acts via a combination of receptors, CB1 and GPR18, to lower IOP and 2) that A9-THC regulation of IOP is sex-dependent, lowering pressure to a greater extent in males than in females. The results add potential new therapeutic targets for the lowering of IOP as a treatment of glaucoma. Lowering IOP remains the chief therapeutic approach to this disease. The decline in IOP induced by A9-THC was very promising at -30%. It is also possible that THC will work cooperatively with another existing therapy.
[0061] In summary, there is evidence that activation of a dual
CBl/GPR18-based signaling system in the mammalian eye lowers IOP. It does so selectively in males of the species tested. Because glaucoma remains a major cause of blindness, with a substantial number of patients unresponsive to conventional treatments, the identification of a novel mechanism to lower IOP is therefore of great therapeutic interest. These results suggest that CB1/GPR18 may serve as a desirable dual target for development of novel ocular hypotensive medications.
[0062] This written description uses examples to disclose the invention and also to enable any person skilled in the art to practice the invention, including making and using any compositions and performing any incorporated methods. The patentable scope of the present disclosure is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.

Claims

WHAT IS CLAIMED IS:
1. A method for activating a dual CBl/GPR18-based signaling system in the eye of a subject in need thereof, the method comprising administering to the subject at least one activator for targeting a CB 1 receptor in the eye and at least one activator for targeting a GPR18 receptor in the eye.
2. The method of claim 1, wherein the least one activator for targeting the CBl receptor and at least one activator for targeting the GPR18 receptor are the same activator, functioning as a dual activator.
3. The method of claim 2, wherein the dual activator is administered topically to the eye.
4. The method of either claims 2 or 3, wherein the dual activator is Δ9- tetrahydrocannabinol (A9-THC).
5. The method of claim 4, wherein A9-tetrahydrocannabinol (A9-THC) is administered topically to the eye in an amount ranging from about 1 mM to about 20 mM.
6. The method of claim 1 comprising administering to the subject a monoacylglyerol lipase (MAGL) blocker as the activator for targeting the CB 1 receptor in combination with the activator for targeting the GPR18 receptor.
7. The method of claim 6, wherein the activator for targeting the GPR18 receptor is selected from the group consisting of N-arachidonoylglycine (NAGly), abnormal cannabidiol (abnCBD), 5-methyl-4-[(lR,6R)-3-methyl-6-prop-l-en-2- ylcyclohex-2-en- 1 -yljbenzene- 1 ,3 -diol (01602) , 1 ,3 -dimethoxy-5 -methyl-2- [( 1 R,6R)- 3-methyl-6-prop-l-en-2-ylcyclohex-2-en-l-yl]benzene (01918) and combinations thereof.
8. The method of any of claims 1 through 7, wherein the subject is a male mammal.
9. A method for reducing intraocular pressure in a subject in need thereof, the method comprising administering to the subject at least one activator for targeting a CBl receptor in the eye and at least one activator for targeting a GPR18 receptor in the eye.
10. The method of claim 9, wherein the least one activator for targeting the CBl receptor and at least one activator for targeting the GPR18 receptor are the same activator, functioning as a dual activator
11. The method of claim 10, wherein the dual activator is administered topically to the eye.
12. The method of either claims 9 or 10, wherein the dual activator is Δ9- tetrahydrocannabinol (A9-THC).
13. The method of claim 12, wherein A9-tetrahydrocannabinol (A9-THC) is administered topically to the eye in an amount ranging from about 1 mM to about 20 mJVl.
14. The method of claim 9 comprising administering to the subject a monoacylglyerol lipase (MAGL) blocker in combination with the activator targeting the GPR18 receptor.
15. The method of claim 14, wherein the activator targeting the GPR18 receptor is selected from the group consisting of N-arachidonoylglycine (NAGly), abnormal cannabidiol (abnCBD), 5-methyl-4-[(lR,6R)-3-methyl-6-prop-l-en-2- ylcyclohex-2-en- 1 -yljbenzene- 1 ,3 -diol (01602) , 1 ,3 -dimethoxy-5 -methyl-2- [( 1 R,6R)- 3-methyl-6-prop-l-en-2-ylcyclohex-2-en-l-yl]benzene (01918) and combinations thereof.
16. The method of any of claims 9 through 15, wherein the subject is a male mammal.
17. A method for treating glaucoma in a subject in need thereof, the method comprising administering to the subject at least one activator for targeting a CBl receptor in the eye and at least one activator for targeting a GPR18 receptor in the eye.
18. The method of claim 17, wherein the least one activator for targeting the CBl receptor and at least one activator for targeting the GPR18 receptor are the same activator, functioning as a dual activator.
19. The method of claim 18, wherein the dual activator is administered topically to the eye.
20. The method of claim 18, wherein the dual activator is administered topically to the eye in an amount ranging from about 1 mM to about 20 mM.
21. The method of claim 17 comprising administering to the subject a monoacylglyerol lipase (MAGL) blocker in combination with the activator targeting the GPR18 receptor.
22. The method of claim 21, wherein the activator targeting the GPR18 receptor is selected from the group consisting of N-arachidonoylglycine (NAGly), abnormal cannabidiol (abnCBD), 5-methyl-4-[(lR,6R)-3-methyl-6-prop-l-en-2- ylcyclohex-2-en- 1 -yljbenzene- 1 ,3 -diol (01602) , 1 ,3 -dimethoxy-5 -methyl-2- [( 1 R,6R)- 3-methyl-6-prop-l-en-2-ylcyclohex-2-en-l-yl]benzene (01918) and combinations thereof.
23. The method of any of claims 17 through 22, wherein the subject is a male mammal.
PCT/US2018/037727 2017-06-16 2018-06-15 A dual cb1/gpr18-based signaling system in the murine eye regulates intraocular pressure in a sex-dependent manner WO2018232225A1 (en)

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