title: 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.
abstract: Starting from the previously reported 5-HT 7 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-HT 7, 5-HT 1A, and D 2 receptors of compounds 8-31 were assessed, and several compounds displayed 5-HT 7 receptor affinities in the nanomolar range. Among these, N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (25) showed high 5-HT 7 receptor affinity (Ki = 0.58 nM), high selectivity over 5-HT 1A and D 2 receptors (324- and 245-fold, respectively), and agonist properties (maximal effect = 82%, EC 50 = 0.60 microM). 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.
authors.affiliation: Università degli Studi di Bari, Dipartimento Farmaco-Chimico, via Orabona, 4, 70125 Bari, Italy. leopoldo@farmchim.uniba.i.
authors.forename: Marcello
authors.initials: M
authors.lastname: Leopoldo
authors.forename: Enza
authors.initials: E
authors.lastname: Lacivita
authors.forename: Paola
authors.initials: P
authors.lastname: De Giorgio
authors.forename: Claudia
authors.initials: C
authors.lastname: Fracasso
authors.forename: Sara
authors.initials: S
authors.lastname: Guzzetti
authors.forename: Silvio
authors.initials: S
authors.lastname: Caccia
authors.forename: Marialessandra
authors.initials: M
authors.lastname: Contino
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Colabufo
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000187:drug effects*
chemical_list: D010879:Piperazines; D011985:Receptors, Serotonin; C104425:serotonin 7 receptor