Synthesis and biological evaluation of new quinazoline and cinnoline derivatives as potential atypical antipsychotics.
Four new diaza analogues (14, 15, 23, and 24) of the conformationally constrained aminobutyrophenone derivatives QF0104B (5) and QF0108B (6) were synthesized (Schemes 2 and 3), and evaluated for their binding affinities (Table) towards the serotonin 5-HT2A and 5-HT2C, and the dopamine D2 receptors. Among the new compounds, the quinazoline derivative 15 (= 7-{[4-(4-fluorobenzoyl)piperidin-1-yl]methyl}-5,6,7,8-tetrahydroquinazolin-5-one) exhibited the highest affinities towards the serotonin 5-HT2A and dopamine D2 receptors, and it is in the borderline of potential atypical antipsychotics. The cinnoline derivative 23 (= 7-{[4-(4-fluorobenzoyl)piperidin-1-yl]methyl}-5,6,7,8-tetrahydro-3-methylcinnolin-5-one) displayed high selectivity in its binding profile towards the 5-HT2C compared to both the 5-HT2A and D2 receptors.
Alvarado
Mario
M
Departamento de Química Orgánica, Laboratorio de Química Farmacéutica, Facultad de Farmacia, Universidad de Santiago de Compostela, E-15782, Santiago de Compostela, Spain.
Barceló
María
M
Carro
Laura
L
Masaguer
Christian F
CF
Raviña
Enrique
E
D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000378:metabolism; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism
D014150:Antipsychotic Agents; D006574:Heterocyclic Compounds, 2-Ring; D011799:Quinazolines; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; C476282:cinnoline