title: New serotonin 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptor antagonists: synthesis, pharmacology, 3D-QSAR, and molecular modeling of (aminoalkyl)benzo and heterocycloalkanones.
abstract: A series of 52 conformationally constrained butyrophenones have been synthesized and pharmacologically tested as antagonists at 5-HT(2A), 5-HT(2B), and 5-HT(2C) serotonin receptors, useful for dissecting the role of each 5-HT(2) subtype in pathophysiology. These compounds were also a consistent set for the identification of structural features relevant to receptor recognition and subtype discrimination. Six compounds were found highly active (pK(i) > 8.76) and selective at the 5-HT(2A) receptor vs 5-HT(2B) and/or 5-HT(2C) receptors. Piperidine fragments confer high affinity at the 5-HT(2A) receptor subtype, with benzofuranone- and thiotetralonepiperidine as the most selective derivatives over 5-HT(2C) and 5-HT(2B) receptors, respectively; K(i) (2A/2C) and/or K(B) (2A/2B) ratios greater than 100 were obtained. Compounds showing a more pronounced selectivity at 5-HT(2A)/5-HT(2C) than at 5-HT(2A)/5-HT(2B) bear 6-fluorobenzisoxazolyl- and p-fluorobenzoylpiperidine moieties containing one methylene bridging the basic piperidine to the alkanone moiety. An ethylene bridge between the alkanone and the amino moieties led to ligands with higher affinities for the 5-HT(2B) receptor. Significant selectivity at the 5-HT(2B) receptor vs 5-HT(2C) was observed with 1-1[(1-oxo-1,2,3,4-tetrahydro-3-naphthyl)methyl]-4-[3-(p-fluorobenzoyl)propyl]piperazine (more than 100-fold higher). Although piperidine fragments also confer higher affinity at 5-HT(2C) receptors, only piperazine-containing ligands were selective over 5-HT(2A). Moderate selectivity was observed at 5-HT(2C) vs 5-HT(2B) (10-fold) with some compounds bearing a 4-[3-(6-fluorobenzisoxazolyl)]piperidine moiety in its structure. Molecular determinants for antagonists acting at 5-HT(2A) receptors were identified by 3D-QSAR (GRID-GOLPE) studies. Docking simulations at 5-HT(2A) and 5-HT(2C) receptors suggest a binding site for the studied type of antagonists (between transmembrane helices 2, 3, and 7) different to that of the natural agonist serotonin (between 3, 5, and 6).
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universidad de Santiago de Compostela, E-15782, Santiago de Compostela, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Brea
authors.forename: Jordi
authors.initials: J
authors.lastname: Rodrigo
authors.forename: Antonio
authors.initials: A
authors.lastname: Carrieri
authors.forename: Ferran
authors.initials: F
authors.lastname: Sanz
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Cadavid
authors.forename: María J
authors.initials: MJ
authors.lastname: Enguix
authors.forename: María
authors.initials: M
authors.lastname: Villazón
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Mengod
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Caro
authors.forename: Christian F
authors.initials: CF
authors.lastname: Masaguer
authors.forename: Enrique
authors.initials: E
authors.lastname: Raviña
authors.forename: Nuria B
authors.initials: NB
authors.lastname: Centeno
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Loza
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D002090:Butyrophenones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003516:Cycloparaffins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005625:Frontal Lobe / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013270:Stomach / Q000187:drug effects / Q000502:physiology
chemical_list: D002090:Butyrophenones; D003516:Cycloparaffins; D006571:Heterocyclic Compounds; D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists