title: Synthesis, molecular modeling studies, and muscarinic receptor activity of azaprophen analogues.
abstract: Synthesis, radioligand binding, and pharmacologic activities of a series of muscarinic receptor ligands including and related to azaprophen (6-methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate, 1) have been measured to determine activity and selectivity for muscarinic receptor subtypes. Pharmacologic affinities of antagonists were determined as pA2 values for antagonism of methacholine-induced tension responses in guinea pig ileum. Binding affinities were measured by competition against [3H]QNB binding in guinea pig ileum, rat heart and brain, and m1- or m3-transfected Chinese hamster ovary (CHO) cells. The efficacies of muscarinic agonists in brain were determined by the ratio of binding affinities against [3H]QNB or [3H]NMS and [3H]oxotremorine-M ([3H]Oxo-M). Nine muscarinic antagonists, including azaprophen, did not discriminate significantly between the subtypes of muscarinic receptors. KI values for receptor binding for azaprophen (1) were between 8.81 x 10(-11) and 4.72 x 10(-10) M in ileum, heart, brain, and m1- or m3-transfected CHO cells. The alpha- and beta-benzilate esters 5 and 6 are as potent as azaprophen, and diphenylacetate esters 3 and 4 and N-(6)-benzyl alpha-isomer 7 are less potent than azaprophen. Significant stereoselectivity was exhibited with (+)-azaprophen being approximately 200 times more potent than the (-)-enantiomers and the 3 beta-ol isomer 2 being ca. 50 times less potent than azaprophen in all systems. A molecular modeling-molecular mechanics study was conducted to account for the difference. Putative muscarinic agonists (analogues and isomers of 6-methyl-6-azabicyclo[3.2.1]octan-3-ol acetate) did not discriminate muscarinic receptor subtypes with KI values between 2.77 x 10(-6) and 4.33 x 10(-5) M without significant stereoselectivity in the systems examined. The most active analogue was (1R,3R,5S)-6-[1(R)-phenylethyl]-6-azabicyclo[3.2.1]octan-3 alpha-ol acetate. However, efficacies of these putative agonists were in general very low.
authors.affiliation: Research Triangle Institute, Research Triangle Park, North Carolina 27709.
authors.forename: D J
authors.initials: DJ
authors.lastname: Triggle
authors.forename: Y W
authors.initials: YW
authors.lastname: Kwon
authors.forename: P
authors.initials: P
authors.lastname: Abraham
authors.forename: J B
authors.initials: JB
authors.lastname: Pitner
authors.forename: S W
authors.initials: SW
authors.lastname: Mascarella
authors.forename: F I
authors.initials: FI
authors.lastname: Carroll
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006168:Guinea Pigs; D008297:Male; D008958:Models, Molecular; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D011976:Receptors, Muscarinic; D014326:Tropanes