title: Identification and characterization of m1 selective muscarinic receptor antagonists1.
abstract: A series of esters of 1,4-disubstituted tetrahydropyridine carboxylic acids (I) has been synthesized and characterized as potential m1 selective muscarinic receptor antagonists. The affinity of these compounds for the five human muscarinic receptor subtypes (Hm1-Hm5) was determined by the displacement of [3H]-NMS binding using membranes from transfected Chinese hamster ovarian cells. One of the most potent and selective compounds of this series is an analogue of I [11, R1 = (CH2)5CH3], which has an IC50 value of 27.3 nM at the m1 receptor and possesses 100-fold (m2), 48-fold (m3), 74-fold (m4), and 19-fold (m5) selectivities at the other receptors. Thus, this analogue appears to be more selective on the basis of binding than the prototypical m1 antagonist, pirenzepine. Functional data, such as the inhibition of carbachol-stimulated phosphatidylinositol hydrolysis, on selected analogues confirmed the muscarinic antagonistic properties of this chemical series.
authors.affiliation: Departments of Medicinal Chemistry and Neuroscience Therapeutics, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Augelli-Szafran
authors.forename: C J
authors.initials: CJ
authors.lastname: Blankley
authors.forename: J C
authors.initials: JC
authors.lastname: Jaen
authors.forename: D W
authors.initials: DW
authors.lastname: Moreland
authors.forename: C B
authors.initials: CB
authors.lastname: Nelson
authors.forename: J R
authors.initials: JR
authors.lastname: Penvose-Yi
authors.forename: R D
authors.initials: RD
authors.lastname: Schwarz
authors.forename: A J
authors.initials: AJ
authors.lastname: Thomas
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D018727:Muscarinic Antagonists / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology; D013329:Structure-Activity Relationship