Brasili L, Pigini M, Marucci G, Quaglia W, Malmusi L, Lanier S M, Lanier B
Dípartimento di Scienze Farmaceutiche, Università di Modena, Italy.
Bioorg Med Chem. 1995 Nov;3(11):1503-9. doi: 10.1016/0968-0896(95)00132-z.
To characterize the structure-activity relationship between alpha 1-adrenergic receptors and the family of imidazoline/guanidinium receptive sites (IGRS), we synthesized and characterized a series of analogues of cirazoline, an imidazoline with high affinity for alpha 1-adrenergic receptors and IGRS. Analysis of potency, affinity and efficacy of the synthesized molecules indicate different structure-activity relationships for IGRS and alpha-adrenergic receptors. Cirazoline exhibits a 25-fold higher affinity for IGRS (pKi 7.9) than for alpha 1-adrenergic receptors. Replacement of the cyclopropyl ring with an isopropoxy group resulted in a molecule that was 20-fold more selective for alpha 1-adrenergic receptors than for IGRS, i.e. a 500-fold increase in selectivity relative to cirazoline. The unsubstituted derivative 3 and the methyl and allyl substituted analogues 4 and 12 are of particular interest: compounds 3 and 4 recognize IGRS with high affinity (pKi 7.83 and 8.17) and high selectivity (398 and 123) with respect to the alpha 1-adrenergic receptor; compound 12 also recognizes IGRS with high affinity (pKi 8.08) and high selectivity (228 and 138) with respect to the alpha 2B and alpha 2C-adrenergic receptor subtypes. Thanks to their IGRS selectivity, these compounds represent novel and valuable pharmacological tools for the characterization and elucidation of the physiological role of these novel sites.
为了表征α1 - 肾上腺素能受体与咪唑啉/胍基受体位点家族（IGRS）之间的构效关系，我们合成并表征了一系列西拉唑啉类似物。西拉唑啉是一种对α1 - 肾上腺素能受体和IGRS具有高亲和力的咪唑啉。对合成分子的效能、亲和力和效力分析表明，IGRS和α - 肾上腺素能受体具有不同的构效关系。西拉唑啉对IGRS（pKi 7.9）的亲和力比对α1 - 肾上腺素能受体高25倍。用异丙氧基取代环丙基环得到的分子对α1 - 肾上腺素能受体的选择性比对IGRS高20倍，即相对于西拉唑啉，选择性增加了500倍。未取代的衍生物3以及甲基和烯丙基取代的类似物4和12特别令人感兴趣：化合物3和4对IGRS具有高亲和力（pKi 7.83和8.17），并且相对于α1 - 肾上腺素能受体具有高选择性（398和123）；化合物12对IGRS也具有高亲和力（pKi 8.08），并且相对于α2B和α2C - 肾上腺素能受体亚型具有高选择性（228和138）。由于它们对IGRS的选择性，这些化合物代表了用于表征和阐明这些新位点生理作用的新型且有价值的药理学工具。
