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Structural Modifications of N-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-Aryl-1-piperazinehexanamides: Influence on Lipophilicity and 5-HT7 Receptor Activity. Part III

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journal contribution
posted on 25.09.2008, 00:00 by Marcello Leopoldo, Enza Lacivita, Paola De Giorgio, Claudia Fracasso, Sara Guzzetti, Silvio Caccia, Marialessandra Contino, Nicola A. Colabufo, Francesco Berardi, Roberto Perrone
Starting from the previously reported 5-HT7 receptor agents 4−7 with N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamide structure, the 1-(2-methylthiophenyl)-, 1-(2-diphenyl)-, 1-(2-isopropylphenyl)-, and 1-(2-methoxyphenyl)piperazine derivatives 8−31 were designed with the primary aim to obtain new compounds endowed with suitable physicochemical properties for rapid and extensive penetration into the brain. The affinities for 5-HT7, 5-HT1A, and D2 receptors of compounds 8−31 were assessed, and several compounds displayed 5-HT7 receptor affinities in the nanomolar range. Among these, N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (25) showed high 5-HT7 receptor affinity (Ki = 0.58 nM), high selectivity over 5-HT1A and D2 receptors (324- and 245-fold, respectively), and agonist properties (maximal effect = 82%, EC50 = 0.60 μM). After intraperitoneal injection in mice, 25 rapidly reached the systemic circulation and entered the brain. Its brain concentration−time profile paralleled that in plasma, indicating that 25 rapidly and freely distributes across the blood−brain barrier. Compound 25 underwent N-dealkylation to the corresponding 1-arylpiperazine metabolite.

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