title: Structural modifications to tetrahydropyridine-3-carboxylate esters en route to the discovery of M5-preferring muscarinic receptor orthosteric antagonists.
abstract: The M5 muscarinic acetylcholine receptor is suggested to be a potential pharmacotherapeutic target for the treatment of drug abuse. We describe herein the discovery of a series of M5-preferring orthosteric antagonists based on the scaffold of 1,2,5,6-tetrahydropyridine-3-carboxylic acid. Compound 56, the most selective compound in this series, possesses an 11-fold selectivity for the M5 over M1 receptor and shows little activity at M2-M4. This compound, although exhibiting modest affinity (K(i) = 2.24 μM) for the [(3)H]N-methylscopolamine binding site on the M5 receptor, is potent (IC50 = 0.45 nM) in inhibiting oxotremorine-evoked [(3)H]DA release from rat striatal slices. Further, a homology model of human M5 receptor based on the crystal structure of the rat M3 receptor was constructed, and docking studies of compounds 28 and 56 were performed in an attempt to understand the possible binding mode of these novel analogues to the receptor.
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States. gzheng@uams.edu
authors: Guangrong
authors: G
authors: Zheng
authors: Andrew M
authors: AM
authors: Smith
authors: Xiaoqin
authors: X
authors: Huang
authors: Karunai L
authors: KL
authors: Subramanian
authors: Kiran B
authors: KB
authors: Siripurapu
authors: Agripina
authors: A
authors: Deaciuc
authors: Chang-Guo
authors: CG
authors: Zhan
authors: Linda P
authors: LP
authors: Dwoskin
mesh_terms: D000818:Animals; D016466:CHO Cells; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004298:Dopamine / Q000378:metabolism; D004952:Esters; D006801:Humans; D066298:In Vitro Techniques; D062105:Molecular Docking Simulation; D018721:Muscarinic Agonists / Q000494:pharmacology; D010095:Oxotremorine / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D043642:Receptor, Muscarinic M5 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D004952:Esters; D018721:Muscarinic Agonists; D011725:Pyridines; D043642:Receptor, Muscarinic M5; D010095:Oxotremorine; D004298:Dopamine
references: Pharmacol Rev. 1998 Jun;50(2):279-90
references: 9647869
references: Neuron. 1988 Jul;1(5):403-10
references: 3272174
references: Curr Protoc Pharmacol. 2010 Mar;Chapter 4:Unit 4.15
references: 22294371
references: Nat Neurosci. 2003 Jan;6(1):51-8
references: 12483218
references: J Med Chem. 2005 Oct 20;48(21):6597-606
references: 16220976
references: Proc Natl Acad Sci U S A. 1988 Jul;85(14):5274-8
references: 2899326
references: J Neurosci. 2002 Aug 1;22(15):6347-52
references: 12151512
references: Br J Pharmacol. 1999 Aug;127(7):1551-8
references: 10455309
references: J Med Chem. 2009 Jun 11;52(11):3445-8
references: 19438238
references: J Med Chem. 2002 Dec 5;45(25):5415-8
references: 12459007
references: Naunyn Schmiedebergs Arch Pharmacol. 1981 Jun;316(3):205-17
references: 7254365
references: Life Sci. 1997;60(13-14):1105-12
references: 9121354
references: Bioorg Med Chem Lett. 2010 Oct 1;20(19):5617-22
references: 20801651
references: Synapse. 2010 Mar;64(3):216-23
references: 19862686
references: J Med Chem. 2002 Jul 4;45(14):3094-102
references: 12086495
references: Eur J Pharmacol. 2007 May 7;562(1-2):92-102
references: 17336285
references: Bioorg Med Chem Lett. 2001 May 7;11(9):1241-3
references: 11354386
references: J Phys Chem B. 2012 Jan 12;116(1):532-41
references: 22185605
references: Br J Pharmacol. 1998 Jul;124(5):883-8
references: 9692772
references: J Biol Chem. 1995 Aug 18;270(33):19532-9
references: 7642637
references: Ann N Y Acad Sci. 1988;537:216-27
references: 3059925
references: J Med Chem. 1999 Feb 11;42(3):356-63
references: 9986705
references: Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):14096-101
references: 11707605
references: Annu Rev Pharmacol Toxicol. 2004;44:423-50
references: 14744253
references: Nature. 2012 Feb 22;482(7386):552-6
references: 22358844
references: N Engl J Med. 2003 Sep 4;349(10):975-86
references: 12954747
references: J Org Chem. 2008 May 16;73(10):3942-5
references: 18412390
references: Life Sci. 2003 Dec 5;74(2-3):345-53
references: 14607263
references: J Neurosci. 2005 Sep 7;25(36):8141-9
references: 16148222
references: J Med Chem. 2006 Sep 21;49(19):5653-63
references: 16970392
references: Eur J Neurosci. 2005 Apr;21(7):1837-46
references: 15869479
references: Nat Rev Drug Discov. 2007 Sep;6(9):721-33
references: 17762886
references: J Clin Pharm Ther. 2009 Dec;34(6):623-9
references: 20175795
references: Pharmacol Ther. 1993 Jun;58(3):319-79
references: 7504306
references: Neurosci Lett. 1990 Jul 3;114(2):154-9
references: 2395528
references: J Neurosci. 2000 Dec 1;20(23):8861-7
references: 11102495
references: J Pharmacol Exp Ther. 1986 Nov;239(2):442-53
references: 3772803
references: Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11452-7
references: 12154229
references: Mol Pharmacol. 1993 Feb;43(2):149-57
references: 8429821
references: Biochem Pharmacol. 1973 Dec 1;22(23):3099-108
references: 4202581
references: Bioorg Med Chem Lett. 2002 Mar 11;12(5):795-8
references: 11859005
references: Bioorg Med Chem Lett. 2010 Jan 15;20(2):558-62
references: 20004578
references: J Neuropsychiatry Clin Neurosci. 1997 Summer;9(3):482-97
references: 9276849
references: Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15312-7
references: 11752469