Synthesis, alpha-adrenoceptors affinity and alpha 1-adrenoceptor antagonistic properties of some 1,4-substituted piperazine derivatives

• Published in: Pharmazie Vol. 66; no. 10; pp. 733 - 739
• Main Authors: Marona, H, Kubacka, M, Filipek, B, Siwek, A, Dybała, M, Szneler, E, Pociecha, T, Gunia, A, Waszkielewicz, A M
• Format: Journal Article
• Language: English
• Published: Germany 01.10.2011
• Subjects: Adrenergic alpha-1 Receptor Antagonists - pharmacology; Adrenergic alpha-Antagonists - metabolism; Animals; Aorta, Thoracic - drug effects; Aorta, Thoracic - metabolism; Biological Assay; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Dose-Response Relationship, Drug; In Vitro Techniques; Indicators and Reagents; Male; Piperazines - metabolism; Piperazines - pharmacology; Radioligand Assay; Rats; Rats, Wistar; Receptors, Adrenergic, alpha - metabolism; Receptors, Adrenergic, alpha-1 - metabolism; Receptors, Adrenergic, alpha-2 - metabolism; Structure-Activity Relationship
• ISSN: 0031-7144
• DOI: 10.1691/ph.2011.1543

A series of different 1,4-substituted piperazine derivatives (1-11) was synthesized. It comprised 1-(substituted-phenoxyalkyl)-4-(2-methoxyphenyl)piperazine derivatives (1-5); 1,4-bis(substituted-phenoxyethyl)piperazine derivatives (6-8) and 1-(substituted-phenoxy)-3-(substituted-phenoxyalkylpiperazin-1-yl)propan-2-ol derivatives (9-11). All compounds were evaluated for affinity toward alpha 1- and alpha 2-receptors by radioligand binding assays on rat cerebral cortex using [3H]prazosin and [3H]clonidine as specific radioligand, respectively. Furthermore alpha 1-antagonistic properties were checked for most promising compounds (1-5 and 10) by means of inhibition of phenylephrine induced contraction in isolated rat aorta. Antagonistic potency stayed in agreement with radioligand binding results. The most active compounds (1-5) displaced [3H]prazosin from cortical binding sites in low nanomolar range (Ki = 2.1-13.1 nM). Compound 10 showed slightly lower affinity for alpha 1-adrenoceptor (Ki = 781 nM). Compounds 2-5 displayed the strongest antagonistic activity with pA2 values ranging from 8.441 to 8.807. Compound 1 gave a pA2 value of 7.868, while compound 10 showed the weakest antagonistic potency, giving a pA2 value of 6.374. 1-[3-(2-Chloro-6-methylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride (5) showed the best alpha 1- affinity properties with a Ki(alpha 1) value of 2.1 nM and it was 61.05 fold more selective toward alpha 1 than alpha 2-receptors. The best properties showed 1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride (4) with a Ki(alpha 1) value of 2.4 nM, a 142.13 fold better selectivity to alpha 1 - over alpha 2-adrenoceptors and the best antagonistic potency (pA2 = 8.807). It is worth to emphasized that all most promising compounds possessed an 1-(o-methoxyphenyl)piperazine moiety which probably plays an important role in the affinity to alpha-adrenoceptors.