title: Synthesis and binding profile of constrained analogues of N-[4-(4-arylpiperazin-1-yl)butyl]-3-methoxybenzamides, a class of potent dopamine D3 receptor ligands.
abstract: We recently reported on a series of N-[4-(4-arylpiperazin-1-yl)butyl]-3-methoxybenzamides, endowed with high affinity for dopamine D(3) receptors, but lacking of selectivity over D(4), D(2), 5-HT(1A), and alpha(1)-receptors. To improve the D(3)-receptor affinity and selectivity, without causing a considerable increasing in the lipophilicity, the flexible butyl linker was replaced by a more conformationally constrained cyclohexyl linker. The new cis- and trans-N-[4-(4-aryl-1-piperazinyl)cyclohexyl]-3-methoxybenzamides (Aryl= 2,3-di-Cl-Ph, 2-CH(3)O-Ph, 4-Cl-Ph, 2,3-di-CH(3)-Ph) were tested in-vitro for their binding affinity for D(3), D(4), D(2), 5-HT(1A), and alpha(1)-receptors. The trans- derivatives were found to be more potent at D(3) receptor than the corresponding cis- isomers, but less potent than the opened counterparts. This reflected negatively on the selectivity over the other studied receptors. Derivative trans-N-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]cyclohexyl}-3-methoxybenzamide (trans-7) showed high D(3)-receptor affinity (K(i)=0.18 nM) and a relevant selectivity over D(4), D(2), 5-HT(1A), and alpha(1)-receptors (>200-fold). This compound was characterized as a full agonist at D(3) receptor when tested in the Eu-GTP binding assay.
authors.affiliation: Università degli Studi di Bari, Dipartimento Farmaco-Chimico, via Orabona 4, 70125 Bari, Italy. leopoldo@farmchim.uniba.it
authors.forename: Marcello
authors.initials: M
authors.lastname: Leopoldo
authors.forename: Enza
authors.initials: E
authors.lastname: Lacivita
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; D001549:Benzamides / Q000138:chemical synthesis / Q000494:pharmacology*; D001667:Binding, Competitive; D016466:CHO Cells; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D006160:Guanosine Triphosphate / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000378:metabolism*; D013134:Spiperone
chemical_list: D001549:Benzamides; D008024:Ligands; D050637:Receptors, Dopamine D3; D013134:Spiperone; D006160:Guanosine Triphosphate