Rzeszotarski W J, McPherson D W, Ferkany J W, Kinnier W J, Noronha-Blob L, Kirkien-Rzeszotarski A
Nova Pharmaceutical Corporation, Baltimore, Maryland 21224-2788.
J Med Chem. 1988 Jul;31(7):1463-6. doi: 10.1021/jm00402a035.
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.
制备了毒蕈碱拮抗剂3-(1-氮杂双环[2.2.2]辛基)α-羟基-α,α-二苯基乙酸酯(3-奎宁环基二苯羟乙酸酯，QNB，1)、3-(1-氮杂双环[2.2.2]辛基)呫吨-9-羧酸酯(3-奎宁环基呫吨-9-羧酸酯，QNX，2)和3-(1-氮杂双环[2.2.2]辛基)α-羟基-α-苯基丙酸酯(3-奎宁环基阿托乳酸酯，QNA，3)的所有光学异构体，并进行了结合和功能测定。在所有情况下，(R)-1-氮杂双环[2.2.2]辛烷-3-醇(3-奎宁环醇)的酯对毒蕈碱型乙酰胆碱受体(M-AChRs)的M1和M2亚群的亲和力均高于其S型对应物。毒蕈碱拮抗剂的醇部分具有S绝对立体化学的QNB(1)、QNX(2)和QNA(3)的对映体对M1-AChRs更具选择性。这种选择性受酸部分的性质以及(对于QNA而言)手性的调节。该系列中最有效的异构体是(R)-QNB。在QNA系列中，醇具有绝对R构型(a)且酸具有R构型(b)的非对映异构体在结合和功能测定中都是最有效的，而(Sa,Rb)-QNA对M-AChRs的M1亚型最具选择性。事实上，后一种非对映异构体对M1-AChRs的效力和选择性与哌仑西平相当。
