Eberlein W G, Engel W, Mihm G, Rudolf K, Wetzel B, Entzeroth M, Mayer N, Doods H N
Trends Pharmacol Sci. 1989 Dec;Suppl:50-4.
The discovery of the M1-selective receptor antagonist pirenzepine was the impetus for a research project directed towards the development of selective muscarinic antagonists. In the pursuit of this objective, compounds with different selectivity profiles have been found. AF-DX 116 was the first cardioselective antagonist synthesized. Subsequently novel M2 receptor antagonists have been discovered with higher potency and selectivity. Moreover, a pirenzepine-type compound UH-AH 37 has been identified that, in contrast to pirenzepine, shows a higher affinity for ileal than for atrial muscarinic receptors. Among tricyclic muscarinic receptor antagonists three different selectivity profiles have been identified, namely: M1 greater than M3 greater than M2, Msm for pirenzepine; M2 greater than M1 greater than M3, Msm for AF-DX 116, AF-DX 384, AQ-RA 741; and Msm congruent to M1 greater than M2, M3 for UH-AH 37 and its (+) enantiomer.
M1选择性受体拮抗剂哌仑西平的发现推动了一项旨在开发选择性毒蕈碱拮抗剂的研究项目。为实现这一目标，已发现具有不同选择性特征的化合物。AF-DX 116是首个合成的心脏选择性拮抗剂。随后发现了效力和选择性更高的新型M2受体拮抗剂。此外，已鉴定出一种哌仑西平类化合物UH-AH 37，与哌仑西平不同，它对回肠毒蕈碱受体的亲和力高于对心房毒蕈碱受体的亲和力。在三环类毒蕈碱受体拮抗剂中，已鉴定出三种不同的选择性特征，即：M1大于M3大于M2，哌仑西平的Msm；M2大于M1大于M3，AF-DX 116、AF-DX 384、AQ-RA 741的Msm；以及Msm等同于M1大于M2、M3，UH-AH 37及其（+）对映体的Msm。
