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6β-Acyloxy(nor)tropanes: Affinities for Antagonist/Agonist Binding Sites on Transfected and Native Muscarinic Receptors
journal contribution
posted on 2000-05-18, 00:00 authored by John W. Daly, Tara H. Gupta, William L. Padgett, Xue-Feng PeiA series of esters of 6β-hydroxynortropane and the N-methyl analogue 6β-tropanol were
synthesized and screened versus binding of an antagonist (quinuclidinyl benzilate) and an
agonist (oxotremorine-M) at sites on human m1-, m2-, m3-, and m4-muscarinic receptors in
transfected cell membranes and on native M1-muscarinic receptors in rat brain membranes
and native M2-muscarinic receptors in rat heart membranes. Most 6β-acyloxy(nor)tropanes
had higher affinity versus oxotremorine-M binding compared to quinuclidinyl benzilate binding
at transfected m1- and native M1-receptors, indicative of agonist activity. 6β-Acetoxynortropane
had Ki values versus oxotremorine-M binding at m1-, m2-, and m4-receptors ranging from 4 to
7 nM. N-Methylation reduced affinity greatly as did increasing the size of the acyl moiety. The
affinity of 6β-benzoyloxynortropane and other analogues with larger acyl moieties was little
affected by N-methylation or in some cases was increased. 6β-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 M2-muscarinic receptors
of heart, but not at transfected m2-muscarinic receptors. Antagonist/agonist binding ratios were
not obtained for transfected m3-receptors, since significant oxotremorine-M binding could not
be detected. 6β-Acyloxy(nor)tropane, two other (nor)tropanes, and the classical muscarinic
agonists had higher affinity versus agonist binding compared to antagonist binding for
transfected m4-receptors. The antagonist/agonist binding ratio method is clearly not always
reliable for predicting agonist activity at muscarinic receptors.