Cervetto L, Demontis G C, Giannaccini G, Longoni B, Macchia B, Macchia M, Martinelli A, Orlandini E
Dipartimento di Scienze Farmaceutiche and Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università di Pisa, 56126 Pisa, Italy.
J Med Chem. 1998 Dec 3;41(25):4933-8. doi: 10.1021/jm9708700.
3-Phenylpiperidines (PPEs) have been thoroughly investigated in view of their interesting dopaminergic activity, and the N-n-propyl substitution has been suggested as the most effective among several PPEs differently substituted on the phenyl ring. In previous studies, we found that the dimethyl substitution on the phenyl ring of N-unsubstituted PPEs provided compounds active toward alpha2-adrenergic receptors (alpha2-ARs), which proved to possess interesting selectivity properties. The high degree of homology between the binding domains of alpha2-ARs and D4-dopaminergic receptors (D4-DARs) prompted us to verify whether this kind of substitution on the aromatic ring might prove to be active against retinal DARs of the D4 subtype. On the basis of these premises, we synthesized the dimethylphenyl-substituted PPEs 4a-f, in which an n-propyl chain is present on the aminic nitrogen. Radioligand binding assays on bovine retina and striatum membranes for D1-like and D2-like DARs indicated that PPEs 4a, 4b, and 4f possess a high affinity and selectivity for the D4-DAR subtype of bovine retina.
鉴于3-苯基哌啶（PPEs）具有有趣的多巴胺能活性，人们对其进行了深入研究，并且在苯环上有不同取代基的几种PPEs中，N-正丙基取代被认为是最有效的。在先前的研究中，我们发现N-未取代的PPEs苯环上的二甲基取代产生了对α2-肾上腺素能受体（α2-ARs）有活性的化合物，这些化合物被证明具有有趣的选择性特性。α2-ARs和D4-多巴胺能受体（D4-DARs）结合域之间的高度同源性促使我们验证这种苯环上的取代是否对D4亚型的视网膜DARs有活性。基于这些前提，我们合成了二甲基苯基取代的PPEs 4a-f，其中氨基氮上存在正丙基链。对牛视网膜和纹状体膜上D1样和D2样DARs进行的放射性配体结合试验表明，PPEs 4a、4b和4f对牛视网膜的D4-DAR亚型具有高亲和力和选择性。
