Roberto Perrone — Page 2

PubMed2003

Synthesis and structure-affinity relationships of 1-[omega-(4-aryl-1-piperazinyl)alkyl]-1-aryl ketones as 5-HT(7) receptor ligands.

Structural requirements for 5-HT(7) receptor affinity and selectivity over that for the 5-HT(1A) receptor were studied on a series of 1-[omega-(4-aryl-1-piperazinyl)alkyl]-1-aryl ketones. The presence of a hydroxy or methoxy substituent on aryl ketone moiety, alkyl chain length, and the nature of N-1-piperazine substituent were explored. 6-[4-(3-Benzisoxazolyl)-1-piperazinyl]-1-(2-hydroxyphenyl)-1-hexanone (40) and its methoxy analogue 43 exhibited high 5-HT(7) receptor affinities (Ki = 2.93 nM and 0.90 nM, respectively) and agonist properties when tested for 5-HT(7) receptor-mediated relaxation of substance P-induced guinea-pig ileum contraction.

Animals↗

PubMed2002

Structure-affinity relationship study on N-[4-(4-arylpiperazin-1-yl)butyl]arylcarboxamides as potent and selective dopamine D(3) receptor ligands.

The benzamide PB12 (N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide) (1), already reported as potent and selective dopamine D(4) receptor ligand, has been modified searching for structural features that could lead to D(3) receptor affinity. Changes in the aromatic ring linked to N-1 piperazine ring led to the identification of 2-methoxyphenyl and 2,3-dichlorophenyl derivatives (compounds 6 and 13) displaying moderate D(3) affinity (K(i) = 145 and 31 nM, respectively). Intermediate alkyl chain elongation in compounds 1, 6, and 13 improved binding affinity for the D(3) receptor and decreased the D(4) affinity (compounds 18-26). Among these latter compounds, the N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-3-methoxybenzamide (19) was further modified with the replacement or of the 2,3-dichlorophenyl moiety (compounds 27-30) or of the 3-methoxyphenyl ring (compounds 31-41). In this way, we identified several high-affinity D(3) ligands (0.13 nM < K(i)'s < 4.97 nM) endowed with high selectivity over D(2), D(4), 5-HT(1A), and alpha(1) receptors. In addition, N-[4-[4-(2,3-dimethylphenyl)piperazin-1-yl]butyl]-3-methoxybenzamide (27) and N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-7-methoxy-2-benzofurancarboxamide (41) appear to be valuable candidates for positron emission tomography (PET) because of their affinity values, lipophilicity properties, and liability of (11)C labeling in the O-methyl position.

Animals↗