receptor allosteric modulator with potential antipsychotic
properties. Neuropsychopharmacology. 201;35:855-869.
Brady A, Jones CK, Bridges TM, et al. Centrally active allosteric
potentiators of the M4 muscarinic acetylcholine receptor reverse
amphetamine-induced hyperlocomotor activity in rats. J Pharm Exp
Ther. 2008;327;941-953.
Analog 19p exhibited a 2.5 to 5-fold improvement in rat M4 PAM
activity when compared to 1a or 2, respectively. While this analog
displayed a 2-fold increase in rat CLhep and was more bound to rat
plasma proteins than 1a, all other protein binding values were
similar. Moreover, 19p possessed improved brain:plasma Kp and
Kp,uu values in relation to 1a. Although this endeavor did not
deliver M4 PAMs with the desired DMPK profiles to advance as
potential development candidates, it did garner insights to further
our goals, which will be disclosed in due course.
9.
10. Byun NE, Grannan M, Bubser M, et al. Antipsychotic drug-like
effects of the selective M4 muscarinic acetylcholine receptor
positive
allosteric
modulator
VU0152100.
Neuropsychopharmacology. 2014;39:1578-1593.
11. Bubser M, Bridges TM, Dencker D, et al. Selective activation of M4
muscarinic acetylcholine receptors reverses MK-801-induced
behavioral impairments and enhances associative learning in
rodents. ACS Chem Neurosci. 2014;5:920-942.
Acknowledgments
12. Melancon BJ, Wood MR, Noetzel MJ, et al. Optimization of M4
positive allosteric modulators (PAMs): The discovery of
BU0476406, a non-human primate in vivo tool compound for
translational pharmacology. Bioorg Med Chem Lett. 2017;27:2296-
2301.
13. Wood MR, Noetzel J, Melancon BH, et al. Discovery of
VU0467485/AZ13713945: An M4 PAM evaluated as a preclinical
candidate for the treatment of Schizophrenia. ACS Med Chem Lett.
2017;8:233-238.
We thank the NIH for funding via the NIH Roadmap Initiative
1x01 MH077607 (C.M.N.), the Molecular Libraries Probe Center
Network (U54MH084659 to C.W.L.) and U01MH087965
(Vanderbilt NCDDG). We also thank William K. Warren, Jr. and
the William K. Warren Foundation who funded the William K.
Warren, Jr. Chain in Medicine (to C.W.L.).
14. Long MF, Engers JL, Chang S, et al. Discovery of a novel 2,4-
dimethylquinolin-6-carboxamide M4 positive allosteric modulator
(PAM) chemotype via scaffold hopping. Bioorg Med Chem Lett.
2017;27:4999-5001.
15. Temple KJ, Engers JL, Long MF, et al. Discovery of a novel 3,4-
dimethylcinnoline carboxamide M4 positive allosteric mosulator
(PAM) chemotype via scaffold hopping. Bioorg Med Chem Lett.
2019, 19, article 126678.
16. Temple KJ, Long MF, Engers JL, et al. Development of structurally
distinct tricyclic M4 positive allosteric modulator (PAM). Bioorg
Med Chem Lett. Manuscript submitted.
17. Fink DM, Strupczewski JT. Preparation of 6-fluorobenziothiazoles
via a regioselective nucleophilic aromatic substitution reaction.
Tetrahedron Lett. 199;34:6525-6528.
18. Pollak A, Stanovnki B, Tišler M. Synthesis of pyridazine
derivatives – XVI: Methyl substituted imadazo(1,2-b)pyridazines
by synthesis and hemolytic methylation. Tetrahedron.
1968;24:2623-2629.
19. Soria-Arteche O, Hernández-Campos A, Yépez-Mulia L, et al.
Synthesis and antiprotozoal activity of nitazoxanide-N-
methylbenzimidazole hybrids. Bioorg Med Chem Lett.
2013;23:6838-3841.
20. Zhang M, Zhang Y, Song M, et al. Structure-based discovery and
optimization of benzo[d]isoxaole derivatives as potent and selective
BET inhibitors for potential treatment of castration-resistant
prostate cancer (CRPC). J Med Chem. 2018;6:3037-3058.
References and notes
1.
2.
Shen W, Plotkin JL, Francardo V, et al. M4 Muscarinic receptor
signaling ameliorates striatal plasticity deficits in models of L-
DOPA-induced dyskinesia. Neuron. 2015;88:762-773.
Pancani T, Foster DJ, Moehle MS, et al. Allosteric activation of M4
muscarinic receptors improve behavioral and physiological
alteration in early symptomatic YAC128 mice. Proc Natl Acad Sci
USA. 2015;112:14078-14083.
3.
4.
Bridges TM, LeBois EP, Hopkins CR, et al. The antipsychotic
potential of muscarinic allosteric modulation. Drug News Perspect.
2010;23:229-240.
Foster DJ, Wilson JM, Wess J, et al. Antipsychotic-like effects of
M4 positive allosteric modulators are mediated by CB2 receptor-
dependent inhibition of dopamine release. Neuron. 2016;91:1244-
1252.
5.
Jones CK, Byun N, Bubser M. Muscarinic and nicotinic
acetylcholine receptor agonists and allosteric modulators for the
treatment
2012;37:16-42.
Farrell M, Roth BL. Allosteric antipsychotics: M4 muscarinic
potentiators as novel treatments for schizophrenia.
Neuropsychopharmacology. 2010;35:851-852.
Chan WY, McKinzie DL, Bose S, et al. Allosteric modulation of
the muscarinic M4 receptor as an approach to treating
schizophrenia. Proc Natl Acad Sci USA. 2008;105:10978-10983.
Leach K, Loiacono RE, Felder CC, et al. Molecular mechanisms of
action and in vivo validation of an M4 muscarinic acetylcholine
of
schizophrenia.
Neuropsychopharmacology.
6.
7.
8.
Highlights
Discovery of two novel tricyclic-based M4
PAMs
Utility of scaffold hopping to improve
potency/properties/DMPK
Balanced human and rat M4 PAM potency
Rare 8,9-dimethyl-8H-pyrazolo[3,4-
h]quinazoline and 1-methyl-1H-
[1,2,3]triazolo[4,5-h]quinazoline cores