N-[2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide:  A Potent and Selective Dopamine D4 Ligand

• Published in: Journal of medicinal chemistry Vol. 41; no. 24; pp. 4903 - 4909
• Main Authors: Perrone, Roberto, Berardi, Francesco, Colabufo, Nicola A, Leopoldo, Marcello, Tortorella, Vincenzo
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 19.11.1998
• Subjects: Animals; Benzamides - chemical synthesis; Benzamides - chemistry; Benzamides - metabolism; Biological and medical sciences; Catecholaminergic system; Cell Line; Cerebral Cortex - metabolism; Humans; Insecta; Ligands; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - metabolism; Radioligand Assay; Rats; Receptors, Dopamine D2 - biosynthesis; Receptors, Dopamine D2 - metabolism; Receptors, Dopamine D4; Structure-Activity Relationship; Human; D4 Dopamine receptor; Ligand; Benzene derivatives; α1-Adrenergic receptor; Selectivity; In vitro; Biological fixation; 5-HT1A Serotonine receptor; Structure activity relation; Chlorine Organic compounds; Affinity; Carboxamide; Piperazine derivatives; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm981041x

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-[ω-[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 α1 receptors.