RESUMEN
Selective dopamine D(3) receptor (D(3)R) antagonists prevent reinstatement of drug-seeking behavior and decrease the rewarding effects of contextual cues associated with drug intake preclinically, suggesting that they may reduce drug craving in humans. GSK598809 is a selective D(3)R antagonist recently progressed in Phase I trials. The aim of this study was to establish a model, based on the determination of the occupancy of brain D(3)Rs (O(D(3))(R)) across species, to predict the ability of GSK598809 to reduce nicotine-seeking behavior in humans, here assessed as cigarette craving in smokers. Using ex vivo [(125)I](R)-trans-7-hydroxy-2-[N-propyl-N-(3'-iodo-2'-propenyl)amino] tetralin ([(125)I]7OH-PIPAT) autoradiography and [(11)C]PHNO positron emission tomography, we demonstrated a dose-dependent occupancy of the D(3)Rs by GSK598809 in rat, baboon, and human brains. We also showed a direct relationship between O(D(3))(R) and pharmacokinetic exposure, and potencies in line with the in vitro binding affinity. Likewise, GSK598809 dose dependently reduced the expression of nicotine-induced conditioned place preference (CPP) in rats, with an effect proportional to the exposure and O(D(3))(R) at every time point, and 100% effect at O(D(3))(R) values î¶72%. In humans, a single dose of GSK598809, giving submaximal levels (72-89%) of O(D(3))(R), transiently alleviated craving in smokers after overnight abstinence. These data suggest that either higher O(D(3))(R) is required for a full effect in humans or that nicotine-seeking behavior in CPP rats only partially translates into craving for cigarettes in short-term abstinent smokers. In addition, they provide the first clinical evidence of potential efficacy of a selective D(3)R antagonist for the treatment of substance-use disorders.
Asunto(s)
Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Comportamiento de Búsqueda de Drogas/fisiología , Receptores de Dopamina D3/metabolismo , Fumar/tratamiento farmacológico , Fumar/metabolismo , Investigación Biomédica Traslacional/métodos , Adulto , Animales , Células CHO , Cricetinae , Cricetulus , Antagonistas de Dopamina/farmacología , Antagonistas de Dopamina/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Neurológicos , Papio anubis , Unión Proteica/fisiología , Ratas , Receptores de Dopamina D3/antagonistas & inhibidores , Cese del Hábito de Fumar/métodosAsunto(s)
Estimulantes del Apetito/química , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Ghrelina/antagonistas & inhibidores , Hidrazinas/química , Hidrazinas/farmacología , Receptores de Ghrelina , Animales , Estimulantes del Apetito/farmacocinética , Estimulantes del Apetito/farmacología , Dicroismo Circular , Femenino , Ghrelina/metabolismo , Hidrazinas/farmacocinética , Ligandos , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Receptores de Ghrelina/antagonistas & inhibidores , Relación Estructura-ActividadAsunto(s)
Hidrazinas/química , Receptores de Ghrelina/antagonistas & inhibidores , Línea Celular , Evaluación Preclínica de Medicamentos , Trastornos de Alimentación y de la Ingestión de Alimentos/tratamiento farmacológico , Humanos , Hidrazinas/síntesis química , Hidrazinas/uso terapéutico , Receptores de Ghrelina/metabolismo , Relación Estructura-ActividadRESUMEN
The lead optimization process to identify new selective dopamine D(3) receptor antagonists is reported. DMPK parameters and binding data suggest that selective D(3) receptor antagonists as potential PET ligands might have been identified.
Asunto(s)
Imidazolidinas/química , Receptores de Dopamina D3/antagonistas & inhibidores , Animales , Encéfalo/efectos de los fármacos , Química Orgánica/métodos , Química Farmacéutica/métodos , Antagonistas de los Receptores de Dopamina D2 , Humanos , Imidazolidinas/síntesis química , Imidazolidinas/farmacología , Concentración 50 Inhibidora , Ligandos , Modelos Químicos , Tomografía de Emisión de Positrones , Ratas , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Relación Estructura-Actividad , PorcinosRESUMEN
The synthesis and SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported.