A series of esters of 6 beta-hydroxynortropane and the N-methyl analogue 6 beta-tropanol were synthesized and screened versus binding of an antagonist (quinuclidinyl benzilate) and an agonist (oxotremorine-M) at sites...
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A series of esters of 6 beta-hydroxynortropane and the N-methyl analogue 6 beta-tropanol were synthesized and screened versus binding of an antagonist (quinuclidinyl benzilate) and an agonist (oxotremorine-M) at sites on human m(1)-, m(2)-, m(3)-, and m(4)-muscarinic receptors in transfected cell membranes and on native M-1-muscarinic receptors in rat brain membranes and native M-2-muscarinic receptors in rat heart membranes. Most 6 beta-acyloxy(nor)tropanes had higher affinity versus oxotremorine-M binding compared to quinuclidinyl benzilate binding at transfected m(1)- and native M-1-receptors, indicative of agonist activity. 6 beta-Acetoxynortropane had K-i values versus oxotremorine-M binding at m(1)-, m(2)-, and m(4)-receptors ranging from 4 to 7 nM. N-Methylation reduced affinity greatly as did increasing the size of the acyl moiety. The affinity of 6 beta-benzoyloxynortropane and other analogues with larger acyl moieties was little affected by N-methylation or in some cases was increased. 6 beta-Acyloxy(nor)tropanes and classical muscarinic agonists, such as muscarine and oxotremorine, had higher affinity versus oxotremorine-M binding compared to quinuclidinyl benzilate binding at native M-2-muscarinic receptors of heart, but not at transfected m(2)-muscarinic receptors. Antagonist/agonist binding ratios were not obtained for transfected m(3)-receptors, since significant oxotremorine-M binding could not be detected. 6 beta-Acyloxy(nor)tropane, two other (nor)tropanes, and the classical muscarinic agonists had higher affinity versus agonist binding compared to antagonist binding for transfected m(4)-receptors. The antagonist/agonist binding ratio method is clearly not always reliable for predicting agonist activity at muscarinic receptors.
A series of derivatives of the known M-1 selective muscarinic receptor agonist McN-A-343 (1) was designed with the aim of investigating the effects of structural variations on both the butynyl chain and the phenyl rin...
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A series of derivatives of the known M-1 selective muscarinic receptor agonist McN-A-343 (1) was designed with the aim of investigating the effects of structural variations on both the butynyl chain and the phenyl ring of 1. The butynyl chain was replaced with an aromatic spacer, and the effects of such a modification on the stereoelectronic properties of the molecules were theoretically studied and considered compatible with muscarinic receptor affinity. Substituents on the phenyl ring of 1 were selected so as to vary their electronic and hydrophobic properties. This design strategy did not produce muscarinic M-1 receptor agonists more potent than the prototype 1, even if some analogues displayed functional selectivity for different muscarinic receptor subtypes. Compounds 3 and 7 were selective agonists towards muscarinic M-3 receptors, while compounds 14, 16 and 18 were selective muscarinic M-2 receptor agonists. The most interesting derivative was 8, a full agonist at muscarinic M-3 receptors devoid of activity at both muscarinic M-1 and M-2 subtypes. The pharmacological profile of the series was further characterized by studying the anticholinesterase and miotic activities of some representative compounds. Compounds 3-8 turned out to be weak acetylcholinesterase inhibitors, while derivatives 4, 6, 8 and ii were able to significantly reduce the pupillary diameter in rabbit, indicating 8 as an effective miotic agent, (C) 2000 Elsevier Science Ltd. All rights reserved.
Rational drug design utilizing a receptor homology model of the human muscarinic M-1 receptor led to the discovery of the highly potent (K-i = 2 nM), efficacious, and in vivo functionally-selective M-1 agonist, WAY-13...
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Rational drug design utilizing a receptor homology model of the human muscarinic M-1 receptor led to the discovery of the highly potent (K-i = 2 nM), efficacious, and in vivo functionally-selective M-1 agonist, WAY-132983. (C) 1999 Elsevier Science Ltd. All rights reserved.
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