Synthesis and binding affinity of potential atypical antipsychotics with the tetrahydroquinazolinone motif.
A series of 8 new tetrahydroquinazolinone derivatives was synthesized and evaluated for binding affinity to D2 and 5-HT2A human receptors; in addition, some properties related to blood-brain barrier penetration were calculated. From the results of these assays, three compounds were selected for further binding tests on D1, D3, and 5-HT2C human receptors, which are thought to be involved in schizophrenia. From these data, compound 19b emerged as the most promising candidate based on its good binding affinities for D1, D2, and D3 receptors, high affinity for 5-HT2A, low affinity for 5-HT2C receptors, and a Meltzer's ratio characteristic of an atypical antipsychotic profile.
Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, E-15782, Santiago de Compostela, Spain.
Laura
L
Carro
Enrique
E
Raviña
Eduardo
E
Domínguez
José
J
Brea
María I
MI
Loza
Christian F
CF
Masaguer
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000737:chemistry / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy
D014150:Antipsychotic Agents; D052999:Quinazolinones; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3