Affinity and selectivity of the optical isomers of 3-quinuclidinyl benzilate and related muscarinic antagonists.
All of the optical isomers of the muscarinic antagonists 3-(1-azabicyclo[2.2.2]octyl) alpha-hydroxy-alpha,alpha-diphenylacetate (3-quinuclidinyl benzilate, QNB, 1) 3-(1-azabicyclo[2.2.2]octyl) xanthene-9-carboxylate (3-quinuclidinyl xanthene-9-carboxylate, QNX, 2), and 3-(1-azabicyclo[2.2.2]ocytl) alpha-hydroxy-alpha-phenylpropionate (3-quinuclidinyl atrolactate, QNA, 3) were prepared and studied in binding and functional assays. In all instances the esters of (R)-1-azabicyclo[2.2.2]octan-3-ol (3-quinuclidinol) had greater affinity for the M1 and M2 subpopulations of muscarinic acetylcholine receptors (M-AChRs) than did their S counterparts. The enantiomers of QNB (1), QNX (2), and QNA (3) in which the alcoholic portion of the muscarinic antagonists had the S absolute stereochemistry were more selective for the M1-AChRs. This selectivity was modulated by the nature and, in the case of QNA, the chirality of the acid portion. The most potent isomer in the series was (R)-QNB. In the QNA series the diastereoisomer with the absolute R configuration of the alcohol (a) and the R configuration of the acid (b) was the most potent in both binding and functional assays whereas (Sa,Rb)-QNA was the most selective for the M1 subtype of M-AChRs. In fact, the latter diastereomer was as potent and selective as pirenzepine for M1-AChRs.
Rzeszotarski
W J
WJ
Nova Pharmaceutical Corporation, Baltimore, Maryland 21224-2788.
McPherson
D W
DW
Ferkany
J W
JW
Kinnier
W J
WJ
Noronha-Blob
L
L
Kirkien-Rzeszotarski
A
A
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D002417:Cattle; D055598:Chemical Phenomena; D002621:Chemistry; D003342:Corpus Striatum / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D009116:Muscarine / Q000037:antagonists & inhibitors*; D009206:Myocardium / Q000378:metabolism; D010890:Pirenzepine / Q000378:metabolism; D011812:Quinuclidines / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D011813:Quinuclidinyl Benzilate / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000067956:Adenylyl Cyclase Inhibitors; D007295:Inositol Phosphates; D011812:Quinuclidines; D011976:Receptors, Muscarinic; D010890:Pirenzepine; D011813:Quinuclidinyl Benzilate; D009116:Muscarine