Bolognesi M L, Budriesi R, Chiarini A, Poggesi E, Leonardi A, Melchiorre C
Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
J Med Chem. 1998 Nov 19;41(24):4844-53. doi: 10.1021/jm9810654.
Prazosin-related quinazolines 4-20 were synthesized, and their biological profiles at alpha1-adrenoreceptor subtypes were assessed by functional experiments in isolated rat vas deferens (alpha1A), spleen (alpha1B), and aorta (alpha1D) and by binding assays in CHO cells expressing human cloned alpha1-adrenoreceptor subtypes. The replacement of piperazine and furan units of prazosin (1) by 1, 6-hexanediamine and phenyl moieties, respectively, affording 3-20, markedly affected both affinity and selectivity for alpha1-adrenoreceptor subtypes in functional experiments. Cystazosin (3), bearing a cystamine moiety, was a selective alpha1D-adrenoreceptor antagonist being 1 order of magnitude more potent at alpha1D-adrenoreceptors (pA2, 8.54 +/- 0.02) than at the alpha1A- (pA2, 7.53 +/- 0.01) and alpha1B-subtypes (pA2, 7.49 +/- 0. 01). The insertion of substituents on the furan ring of 3, as in compounds 4 and 5, did not improve the selectivity profile. The simultaneous replacement of both piperazine and furan rings of 1 gave 8 which resulted in a potent, selective alpha1B-adrenoreceptor antagonist (85- and 15-fold more potent than at alpha1A- and alpha1D-subtypes, respectively). The insertion of substituents on the benzene ring of 8 affected, according to the type and the position of the substituent, affinity and selectivity for alpha1-adrenoreceptors. Consequently, the insertion of appropriate substituents in the phenyl ring of 8 may represent the basis of designing new selective ligands for alpha1-adrenoreceptor subtypes. Interestingly, the finding that polyamines 11, 16, and 20, bearing a 1,6-hexanediamine moiety, retained high affinity for alpha1-adrenoreceptor subtypes suggests that the substituent did not give rise to negative interactions with the receptor. Finally, binding assays performed with selected quinazolines (2, 3, and 14) produced affinity results, which were not in agreement with the selectivity profiles obtained from functional experiments. This rather surprising and unexpected finding may be explained by considering neutral and negative antagonism.
合成了与哌唑嗪相关的喹唑啉类化合物4 - 20，并通过在离体大鼠输精管（α1A）、脾脏（α1B）和主动脉（α1D）中的功能实验以及在表达人克隆α1 - 肾上腺素能受体亚型的CHO细胞中的结合试验，评估了它们在α1 - 肾上腺素能受体亚型上的生物学特性。分别用1,6 - 己二胺和苯基部分取代哌唑嗪（1）的哌嗪和呋喃单元，得到化合物3 - 20，这在功能实验中显著影响了对α1 - 肾上腺素能受体亚型的亲和力和选择性。带有胱胺部分的胱唑嗪（3）是一种选择性α1D - 肾上腺素能受体拮抗剂，在α1D - 肾上腺素能受体上的效力（pA2，8.54±0.02）比在α1A - （pA2，7.53±0.01）和α1B - 亚型（pA2，7.49±0.01）上高1个数量级。如化合物4和5那样，在3的呋喃环上引入取代基并没有改善选择性。同时取代1的哌嗪环和呋喃环得到化合物8，它是一种强效、选择性的α1B - 肾上腺素能受体拮抗剂（分别比在α1A - 和α1D - 亚型上的效力高85倍和15倍）。根据取代基的类型和位置，在8的苯环上引入取代基会影响对α1 - 肾上腺素能受体的亲和力和选择性。因此，在8的苯环上引入合适的取代基可能是设计新型α1 - 肾上腺素能受体亚型选择性配体的基础。有趣的是，带有1,6 - 己二胺部分的多胺类化合物11、16和20对α1 - 肾上腺素能受体亚型保持高亲和力这一发现表明该取代基不会与受体产生负面相互作用。最后，用选定的喹唑啉类化合物（2、3和14）进行的结合试验产生的亲和力结果与从功能实验中获得的选择性特征不一致。考虑中性和负性拮抗作用可能可以解释这一相当令人惊讶和意想不到的发现。
