title: N-[2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide: a potent and selective dopamine D4 ligand.
abstract: A series of new 1-aryl-4-alkylpiperazines containing a terminal benzamide fragment or a tetralin-1-yl nucleus on the alkyl chain were synthesized and tested for binding at cloned human dopamine D4 and D2 receptor subtypes. A SAFIR (structure-affinity relationship) study on this series is herein discussed. The most relevant D4 receptor affinities were displayed by N-[omega-[4-arylpiperazin-1-yl]alkyl]-methoxybenzamides (compounds 5, 16-20), their IC50 values ranging between 0.057 and 7.8 nM. Among these, N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide (17) emerged since it exhibited very high affinity for dopamine D4 receptor (IC50 = 0.057 nM) with selectivity of >10 000 for the D4 versus the D2 receptor; compound 17 was also selective versus serotonin 5-HT1A and adrenergic alpha1 receptors.
authors.affiliation: Dipartimento Farmaco-Chimico, Universitá di Bari, via Orabona, 4, 70126 Bari, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Perrone
authors.forename: F
authors.initials: F
authors.lastname: Berardi
authors.forename: N A
authors.initials: NA
authors.lastname: Colabufo
authors.forename: M
authors.initials: M
authors.lastname: Leopoldo
authors.forename: V
authors.initials: V
authors.lastname: Tortorella
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism; D006801:Humans; D007313:Insecta; D008024:Ligands; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis / Q000378:metabolism*; D050638:Receptors, Dopamine D4; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; C493599:DRD4 protein, human; C493601:Drd4 protein, rat; D008024:Ligands; C115935:N-(2-(4-(4-chlorophenyl)piperazin-1-yl)ethyl)-3-methoxybenzamide; D010879:Piperazines; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4