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.
Leopoldo
Marcello
M
Dipartimento Farmaco-Chimico, Università degli Studi di Bari, via Orabona, 4, 70126 Bari, Italy. leopoldo@farmchim.uniba.it
Berardi
Francesco
F
Colabufo
Nicola A
NA
De Giorgio
Paola
P
Lacivita
Enza
E
Perrone
Roberto
R
Tortorella
Vincenzo
V
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3; D011985:Receptors, Serotonin / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D013329:Structure-Activity Relationship
D001549:Benzamides; D001572:Benzofurans; C493593:DRD3 protein, human; C493595:Drd3 protein, rat; D008024:Ligands; C470206:N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-7-methoxy-2-benzofurancarboxamide; C470207:N-(4-(4-(2,3-dimethylphenyl)piperazin-1-yl)butyl)-3-methoxybenzamide; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1