Anticholinergic activity in mice and receptor-binding properties in rats of a series of synthetic tropane derivatives.
A tropane ester, three tropane ethers, atropine and mecamylamine were compared in mice for their anti-muscarinic and anti-nicotinic activity against arecoline-induced tremor and nicotine-induced convulsions, respectively. Their receptor-binding characteristics were studied in neuronal membranes prepared from rat cerebral cortex. The results showed that the tropane ester, 2 alpha R-tropanyl benzylate, was more potent than atropine in its anti-muscarinic activity, but the anti-muscarinic activity of the tropane ethers, 2 alpha-(2',2'-diphenyl-2'-hydroxy-ethoxy)tropane (alpha-DPT) and its two isomers (1R,2 alpha R- and 1S,2 alpha S-) were less potent than that of atropine. In contrast with their anti-muscarinic potency, 2 alpha R-tropanyl benzylate and the three tropane ethers were equipotent in their anti-nicotinic activities. The order of potencies of these compounds to displace the binding of [3H]quinuclidinyl benzylate to brain membranes was similar to that of their anti-muscarinic potencies. The binding of [3H]nicotine to nicotinic receptors from brain was not inhibited by these compounds. Analyses of structure-activity relationships of these compounds suggested that it is the ester groups that determine the anti-muscarinic potencies of 2 alpha R-tropanyl benzylate; their anti-nicotinic activities were independent of the structural changes and of the anti-muscarinic activities of these compounds.
Gao
Z G
ZG
Institute of Pharmacology and Toxicology, Beijing, China.
Cui
W Y
WY
Liu
B Y
BY
Liu
C G
CG
Wang
L
L
D000818:Animals; D001115:Arecoline / Q000633:toxicity; D001921:Brain / Q000378:metabolism; D004336:Drug Antagonism; D005260:Female; D008297:Male; D051379:Mice; D018721:Muscarinic Agonists / Q000633:toxicity; D018727:Muscarinic Antagonists / Q000378:metabolism / Q000494:pharmacology*; D009538:Nicotine / Q000378:metabolism / Q000633:toxicity; D018722:Nicotinic Agonists / Q000633:toxicity; D018733:Nicotinic Antagonists / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014202:Tremor / Q000139:chemically induced / Q000517:prevention & control; D014326:Tropanes / Q000378:metabolism / Q000494:pharmacology*
D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D014326:Tropanes; D001115:Arecoline; D009538:Nicotine