ES2892956T3 - Moduladores alostéricos positivos del receptor muscarínico de acetilcolina M4 - Google Patents

Moduladores alostéricos positivos del receptor muscarínico de acetilcolina M4 Download PDF

Info

Publication number
ES2892956T3
ES2892956T3 ES17866492T ES17866492T ES2892956T3 ES 2892956 T3 ES2892956 T3 ES 2892956T3 ES 17866492 T ES17866492 T ES 17866492T ES 17866492 T ES17866492 T ES 17866492T ES 2892956 T3 ES2892956 T3 ES 2892956T3
Authority
ES
Spain
Prior art keywords
compound
thieno
pyridazin
amine
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
ES17866492T
Other languages
English (en)
Spanish (es)
Inventor
Paul Spearing
Madeline Long
Julie Engers
Craig Lindsley
P Conn
Darren Engers
Alison Gregro
Kayla Temple
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vanderbilt University
Original Assignee
Vanderbilt University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vanderbilt University filed Critical Vanderbilt University
Application granted granted Critical
Publication of ES2892956T3 publication Critical patent/ES2892956T3/es
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Psychiatry (AREA)
  • Anesthesiology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
ES17866492T 2016-11-07 2017-11-07 Moduladores alostéricos positivos del receptor muscarínico de acetilcolina M4 Active ES2892956T3 (es)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201662418668P 2016-11-07 2016-11-07
US201762542626P 2017-08-08 2017-08-08
PCT/US2017/060340 WO2018085813A1 (en) 2016-11-07 2017-11-07 Positive allosteric modulators of the muscarinic acetylcholine receptor m4

Publications (1)

Publication Number Publication Date
ES2892956T3 true ES2892956T3 (es) 2022-02-07

Family

ID=62076441

Family Applications (1)

Application Number Title Priority Date Filing Date
ES17866492T Active ES2892956T3 (es) 2016-11-07 2017-11-07 Moduladores alostéricos positivos del receptor muscarínico de acetilcolina M4

Country Status (8)

Country Link
US (1) US10927126B2 (OSRAM)
EP (1) EP3544961B1 (OSRAM)
JP (1) JP7097623B2 (OSRAM)
CN (2) CN109863139B (OSRAM)
BR (1) BR112018013879A2 (OSRAM)
ES (1) ES2892956T3 (OSRAM)
MA (1) MA46899A (OSRAM)
WO (1) WO2018085813A1 (OSRAM)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GEP20207167B (en) 2016-06-22 2020-10-12 Univ Vanderbilt Positive allosteric modulators of the muscarinic acetylcholine receptor m4
CN109862893B (zh) 2016-11-07 2023-02-17 范德比尔特大学 毒蕈碱型乙酰胆碱受体m4的正向别构调节剂
US11008335B2 (en) 2016-11-07 2021-05-18 Vanderbilt University Positive allosteric modulators of the muscarinic acetylcholine receptor M4
TW201930311A (zh) 2017-12-05 2019-08-01 泛德比爾特大學 蕈毒鹼型乙醯膽鹼受體m4之正向別構調節劑
EP4447953A1 (en) 2021-12-13 2024-10-23 Sage Therapeutics, Inc. Combination of muscarinic receptor positive modulators and nmda positive allosteric modulators
WO2025129082A1 (en) * 2023-12-14 2025-06-19 Vanderbilt University Positive allosteric modulators of the muscarinic acetylcholine receptor m4

Family Cites Families (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5594001A (en) * 1993-04-08 1997-01-14 The Dupont Merck Pharmaceutical Company Polycyclic systems, and derivatives thereof, as neurotransmitter release enhancers useful in the treatment of cognitive disorders
SK124695A3 (en) * 1993-04-08 1996-06-05 Du Pont Merck Pharma Disubstituted polycyclic compounds and their derivatives alone and for treatment, and pharmaceutical compositions on their base
US5679683A (en) 1994-01-25 1997-10-21 Warner-Lambert Company Tricyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
IL112248A0 (en) 1994-01-25 1995-03-30 Warner Lambert Co Tricyclic heteroaromatic compounds and pharmaceutical compositions containing them
US20020168761A1 (en) 2000-01-24 2002-11-14 Gour Barbara J. Peptidomimetic modulators of cell adhesion
US6608053B2 (en) 2000-04-27 2003-08-19 Yamanouchi Pharmaceutical Co., Ltd. Fused heteroaryl derivatives
PT1303306E (pt) 2000-07-27 2006-11-30 Pharmacia Corp Terapia de combinação de antagonista de aldosterona epoxiesteróide e de antagonista beta-adrenérgico para tratamento de insuficiência cardíaca congestiva.
US7291733B2 (en) * 2003-10-10 2007-11-06 Boehringer Ingelheim Pharmaceuticals, Inc. Substituted tricyclic heterocycles and their uses
CA2542076C (en) 2003-10-14 2013-02-26 Arizona Board Of Regents On Behalf Of The University Of Arizona Substituted tricyclic compounds as protein kinase inhibitors
US20090099165A1 (en) 2003-10-14 2009-04-16 Arizona Board Of Regents On Behalf Of The University Of Arizona Protein Kinase Inhibitors
PE20060526A1 (es) 2004-06-15 2006-07-13 Schering Corp Compuestos triciclicos como antagonistas de mglur1
ATE455777T1 (de) * 2004-07-23 2010-02-15 Medicines Co Leipzig Gmbh Substituierte pyridoä3',2':4,5üthienoä3,2- düpyrimidine und pyridoä3',2':4,5üfuroä3,2-dü- pyrimidine zur verwendung als inhibitoren der pda-4 und/oder tnf-alpha freisetzung
EP1619196A1 (de) 2004-07-23 2006-01-25 Curacyte Discovery GmbH Substituierte Pyrido[3',2':4,5]thieno[3,2-d]pyrimidine und Pyrido[3',2':4,5]furo[3,2-d]-pyrimidine zur Verwendung als Inhibitoren der PDA-4 und/oder TNF-alpha Freisetzung
ES2349416T3 (es) * 2004-10-25 2011-01-03 Eli Lilly And Company Tienopiridinas como potenciadores alostéricos del receptor muscarínico m4.
ES2259891B1 (es) 2004-11-30 2007-11-01 Laboratorios Almirall S.A. Nuevos derivados de piridotienopirimidina.
ES2259892B1 (es) 2004-11-30 2007-11-01 Laboratorios Almirall S.A. Nuevos derivados de piridotienopirimidina.
BRPI0519521A2 (pt) * 2004-12-17 2009-02-10 Hoffmann La Roche derivados de tieno-piridina como aumentadores alostÉricos gaba-b
WO2006138418A2 (en) 2005-06-14 2006-12-28 President And Fellows Of Harvard College Improvement of cognitive performance with sirtuin activators
AR059901A1 (es) 2006-03-20 2008-05-07 Bayer Pharmaceuticals Corp Compuestos de tetrahidropiridotienopirimidina utiles para tratar o prevenir trastornos proliferativos celulares.
CA2649543A1 (en) * 2006-04-21 2007-11-01 Amgen Inc. Thieno-[2,3-d]pyrimidine and thieno-pyridazine compounds and methods of use
US20080021063A1 (en) 2006-07-18 2008-01-24 Kazantsev Aleksey G Compositions and methods for modulating sirtuin activity
US7547781B2 (en) 2006-09-11 2009-06-16 Curis, Inc. Quinazoline based EGFR inhibitors containing a zinc binding moiety
ES2656496T3 (es) 2006-12-29 2018-02-27 Rigel Pharmaceuticals, Inc. Triazoles sustituidos útiles como inhibidores de AXL
US20090105240A1 (en) 2007-10-17 2009-04-23 Tomas Mustelin Methods for treating leukemia and myelodysplastic syndrome, and methods for identifying agents for treating same
US20100009934A1 (en) 2008-06-09 2010-01-14 Combinatorx, Incorporated Beta adrenergic receptor agonists for the treatment of b-cell proliferative disorders
CN102498115B (zh) 2009-08-20 2016-12-07 卡鲁斯治疗有限公司 作为磷酸肌醇3-激酶抑制剂的三环杂环化合物
US20110178107A1 (en) 2010-01-20 2011-07-21 Taigen Biotechnology Co., Ltd. Hcv protease inhibitors
WO2012131297A1 (en) * 2011-03-28 2012-10-04 Jonathan Bayldon Baell Pyrido [3',2' :4,5] thieno [3, 2-d] pyrimidin- 4 - ylamine derivatives and their therapeutical use
WO2013040534A1 (en) * 2011-09-16 2013-03-21 Vanderbilt University Substituted 1h-pyrazolo[3',4',4,5]thieno[2,3-b]pyridin-3-amine analogs as positive allosteric modulatiors of the muscarinic acetycholine receptor m4
US20130116241A1 (en) 2011-11-09 2013-05-09 Abbvie Inc. Novel inhibitor compounds of phosphodiesterase type 10a
CN104271132B (zh) 2011-12-21 2018-01-12 科罗拉多大学董事会法人团体 靶向Ral GTP酶的抗癌化合物及使用其的方法
US8697888B2 (en) 2012-01-06 2014-04-15 Vanderbilt University Substituted (1-(methylsulfonyl)azetidin-3-yl)(heterocycloalkyl)methanone analogs as antagonists of muscarinic acetylcholine M1 receptors
WO2013126856A1 (en) * 2012-02-23 2013-08-29 Vanderbilt University Substituted 5-aminothieno[2,3-c]pyridazine-6-carboxamide analogs as positive allosteric modulators of the muscarinic acetylcholine receptor m4
HK1210696A1 (en) 2012-07-11 2016-05-06 Nimbus Iris, Inc. Irak inhibitors and uses thereof
US9056875B2 (en) 2012-08-31 2015-06-16 Vanderbilt University Substituted pyrazolo[3′,4′:4,5]thieno[2,3-C]pyridazin-3-amine analogs as positive allosteric modulators of the muscarinic acetylcholine receptor M4
US9637498B2 (en) 2013-08-23 2017-05-02 Vanderbilt University Substituted thieno[2,3-C]pyridazine-6-carboxamide analogs as positive allosteric modulators of the muscarinic acetylcholine receptor M4
WO2015027204A1 (en) 2013-08-23 2015-02-26 Vanderbilt University Substituted thieno[2,3-b]pyridine-2-carboxamide analogs as positive allosteric modulators of the muscarinic acetylcholine receptor m4
US9981920B2 (en) 2014-06-26 2018-05-29 Rodin Therapeutics, Inc. Inhibitors of histone deacetylase
GEP20207167B (en) 2016-06-22 2020-10-12 Univ Vanderbilt Positive allosteric modulators of the muscarinic acetylcholine receptor m4
CN109862893B (zh) 2016-11-07 2023-02-17 范德比尔特大学 毒蕈碱型乙酰胆碱受体m4的正向别构调节剂
US11008335B2 (en) 2016-11-07 2021-05-18 Vanderbilt University Positive allosteric modulators of the muscarinic acetylcholine receptor M4

Also Published As

Publication number Publication date
EP3544961A4 (en) 2020-05-13
JP7097623B2 (ja) 2022-07-08
CN109863139A (zh) 2019-06-07
JP2019537581A (ja) 2019-12-26
BR112018013879A2 (pt) 2018-12-11
US10927126B2 (en) 2021-02-23
CN116041365A (zh) 2023-05-02
US20190330231A1 (en) 2019-10-31
EP3544961B1 (en) 2021-08-18
EP3544961A1 (en) 2019-10-02
WO2018085813A1 (en) 2018-05-11
CN109863139B (zh) 2023-02-17
MA46899A (fr) 2021-04-14

Similar Documents

Publication Publication Date Title
ES2936827T3 (es) Moduladores alostéricos positivos del receptor muscarínico de acetilcolina M4
ES2892956T3 (es) Moduladores alostéricos positivos del receptor muscarínico de acetilcolina M4
EP3534901B1 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor m4
US10934276B2 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor M4
US10961253B2 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor M4
US10342782B2 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor M4
US10736898B2 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor M4
US11376254B2 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor M4
US10189857B2 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor M4
US20250017935A1 (en) 7,8-dihydro-5h-1,6-naphthyridine derivatives as positive allosteric modulators of the muscarinic acetylcholine receptor m4 for treating neurological and psychiatric disorders
WO2023064588A1 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor m4
WO2018035444A1 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor m4
WO2025129082A1 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor m4
HK40014595B (en) Positive allosteric modulators of the muscarinic acetylcholine receptor m4
HK40014595A (en) Positive allosteric modulators of the muscarinic acetylcholine receptor m4
HK40014598A (en) Positive allosteric modulators of the muscarinic acetylcholine receptor m4
HK40014598B (en) Positive allosteric modulators of the muscarinic acetylcholine receptor m4