Conformationally constrained butyrophenones as new pharmacological tools to study 5-HT 2A and 5-HT 2C receptor behaviours.
This study presents new pharmacological and molecular modelling studies on a recently described series of conformationally constrained butyrophenones. Alignment-free three-dimensional quantitative structure-activity relationship models developed on the basis of GRid Independent descriptors and partial least squares regression analysis, allow feasible predictions of activity of new compounds and reveal structural requirements for optimal affinity, particularly in the case of the 5-HT(2A) receptor. The requirements for the 5-HT(2A) affinity consist in a precise distance between hydrogen bond donor (protonated amino group) and hydrogen bond acceptor groups, as well as an optimal distance between the protonated amino group and the farthest extreme of the compounds. Another significant result has been the characterisation of two structurally similar compounds as interesting pharmacological tools (1-[(4-Oxo-4,5,6,7-tetrahydrobenzo[b]furan-5-yl)ethyl]-4-(6-fluorobenzisoxazol-3-yl)piperidine and 1-[(4-Oxo-4,5,6,7-tetrahydrobenzo[b]furan-6-yl)methyl]-4-(6-fluorobenzisoxazol-3-yl)piperidine). In spite of their structural similarity, the first compound shows clearly higher affinity for the 5-HT(2C) receptor (about 100 fold) and higher Meltzer ratio (1.17 vs. 0.99) than the second. Moreover, the first compound inhibits arachidonic acid release in a biphasic concentration-dependent way in functional experiments at the 5-HT(2A) receptor and it acts as inverse agonist at the 5-HT(2C) receptor, behaviours that are not shown by the second compound.
Facultad de Farmacia, Departamentos de Farmacologi;a, Universidad de Santiago de Compostela, 15782, Santiago de Compostela, Spain.
José
J
Brea
Christian F
CF
Masaguer
María
M
Villazón
M Isabel
MI
Cadavid
Enrique
E
Raviña
Fabien
F
Fontaine
Cristina
C
Dezi
Manuel
M
Pastor
Ferran
F
Sanz
M Isabel
MI
Loza
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D002090:Butyrophenones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D002417:Cattle; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism*
D002090:Butyrophenones; D007295:Inositol Phosphates; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D016718:Arachidonic Acid