10.1021/jm9904001.s001
John W. Daly
John W.
Daly
Tara H. Gupta
Tara H.
Gupta
William L. Padgett
William L.
Padgett
Xue-Feng Pei
Xue-Feng
Pei
6β-Acyloxy(nor)tropanes: Affinities for Antagonist/Agonist Binding Sites on
Transfected and Native Muscarinic Receptors
American Chemical Society
2000
rat heart membranes
Native Muscarinic Receptors
affinity
transfected cell membranes
muscarinic agonists
quinuclidinyl benzilate binding
rat brain membranes
transfected m 1
m 4
K i values
agonist activity
muscarinic receptors
M 2
M 1
transfected m 4
transfected m 3
transfected m 2
2000-05-18 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/6_-Acyloxy_nor_tropanes_Affinities_for_Antagonist_Agonist_Binding_Sites_on_Transfected_and_Native_Muscarinic_Receptors/3684435
A series of esters of 6β-hydroxynortropane and the <i>N</i>-methyl analogue 6β-tropanol were
synthesized and screened versus binding of an antagonist (quinuclidinyl benzilate) and an
agonist (oxotremorine-M) at sites on human m<sub>1</sub>-, m<sub>2</sub>-, m<sub>3</sub>-, and m<sub>4</sub>-muscarinic receptors in
transfected cell membranes and on native M<sub>1</sub>-muscarinic receptors in rat brain membranes
and native M<sub>2</sub>-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 m<sub>1</sub>- and native M<sub>1</sub>-receptors, indicative of agonist activity. 6β-Acetoxynortropane
had <i>K</i><sub>i</sub> values versus oxotremorine-M binding at m<sub>1</sub>-, m<sub>2</sub>-, and m<sub>4</sub>-receptors ranging from 4 to
7 nM. <i>N</i>-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 <i>N</i>-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 M<sub>2</sub>-muscarinic receptors
of heart, but not at transfected m<sub>2</sub>-muscarinic receptors. Antagonist/agonist binding ratios were
not obtained for transfected m<sub>3</sub>-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 m<sub>4</sub>-receptors. The antagonist/agonist binding ratio method is clearly not always
reliable for predicting agonist activity at muscarinic receptors.