Structure-affinity relationship studies on arylpiperazine derivatives related to quipazine as serotonin transporter ligands. Molecular basis of the selectivity SERT/5HT3 receptor.
A series of quipazine derivatives, previously synthesized to probe the 5-HT(3) receptor, was evaluated for its potential interaction with serotonin transporter (SERT). Some of them show nanomolar affinity for the rodent SERT comparable to or slightly higher than quipazine or N-methylquipazine. Subsequently a candidate was selected on the basis of its SERT affinity and submitted to a molecular manipulation of the basic moiety. The structure-affinity relationships obtained provided information on the role of the fused benzene ring of quipazine in the interaction with the SERT binding site and on the stereoelectronic requirements for the interaction of both the heteroaromatic component and the basic moiety. Moreover, the comparison of the structure-affinity relationships obtained in the present work with those concerning the interaction of these heteroarylpiperazine derivatives with 5-HT3 receptor suggested some molecular determinants of the selectivity SERT/5HT3 receptor.
Cappelli
Andrea
A
Dipartimento Farmaco Chimico Tecnologico and European Research Centre for Drug Discovery and Development, Università di Siena, Via A. Moro, 53100 Siena, Italy. cappelli@unisi.it
Giuliani
Germano
G
Gallelli
Andrea
A
Valenti
Salvatore
S
Anzini
Maurizio
M
Mennuni
Laura
L
Makovec
Francesco
F
Cupello
Aroldo
A
Vomero
Salvatore
S
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008297:Male; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D011814:Quipazine / Q000737:chemistry / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D013329:Structure-Activity Relationship
D008024:Ligands; D010879:Piperazines; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin; D011814:Quipazine