6beta-Acetoxynortropane: a potent muscarinic agonist with apparent selectivity toward M2-receptors.

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Pei XF, Gupta TH, Badio B, Padgett WL, Daly JW

6beta-Acetoxynortropane: a potent muscarinic agonist with apparent selectivity toward M2-receptors.

J Med Chem. 1998 Jun 4;41(12):2047-55.

PubMed ID

9622546 [ View in PubMed

]

Abstract

A series of tropane derivatives, related in structure to baogongteng A (1), an alkaloid from a Chinese herb, were synthesized. 6beta-Acetoxynortropane (5) had weak affinity (Ki 22 microM) for central (M1) muscarinic receptors in a [3H]quinuclidinyl benzilate binding assay but had extremely high affinity (Ki 2.6 nM) and selectivity for M2-muscarinic receptors expressed in CHO cells. It had 13-fold lower affinity for M4-receptors, 260-fold lower affinity for M3-receptors, and 8200-fold lower affinity for M1-receptors expressed in CHO cells. The 6beta-carbomethoxy analogue (14) of baogongteng A had only weak affinity for M2-muscarinic receptors, as did 6beta-carbomethoxynortropane (13) and 6beta-acetoxytropane (4). In transfected CHO cells, 6beta-acetoxynortropane (5) was an agonist at M2-receptors, based on a GTP-elicited decrease in affinity, and a full agonist with an IC50 of 11 nM at M4-receptors, based on inhibition of cyclic AMP accumulation, while being a full agonist at M1-receptors with an EC50 of 23 nM and a partial agonist at M3-receptors with an EC50 of 3.6 nM, based in both cases on stimulation of phosphoinositide breakdown. All of the 16 tropane derivatives had weak affinities for central alpha4beta2-nicotinic receptors with 6beta-carbomethoxynortropane (13) having the highest affinity, which was still 150-fold less than that of nicotine. 6beta-Acetoxynortropane (5) represents a potent muscarinic agonist with apparent selectivity toward M2-receptors.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Arecoline	Muscarinic acetylcholine receptor M3	Ki (nM)	5700	N/A	N/A	Details
Carbamoylcholine	Muscarinic acetylcholine receptor M2	IC 50 (nM)	130	N/A	N/A	Details
Carbamoylcholine	Muscarinic acetylcholine receptor M2	Ki (nM)	20	N/A	N/A	Details
Carbamoylcholine	Muscarinic acetylcholine receptor M2	IC 50 (nM)	3100	N/A	N/A	Details
Carbamoylcholine	Muscarinic acetylcholine receptor M4	Ki (nM)	2600	N/A	N/A	Details