RESUMO
In mammals, the master circadian clock synchronizes daily rhythms of physiology and behavior with the day-night cycle. Failure of synchrony, which increases the risk for numerous chronic diseases, can be treated by phase adjustment of the circadian clock pharmacologically, for example, with melatonin, or a CK1δ/ε inhibitor. Here, using in silico experiments with a systems pharmacology model describing molecular interactions, and pharmacokinetic and behavioral experiments in cynomolgus monkeys, we find that the circadian phase delay caused by CK1δ/ε inhibition is more strongly attenuated by light in diurnal monkeys and humans than in nocturnal mice, which are common preclinical models. Furthermore, the effect of CK1δ/ε inhibition strongly depends on endogenous PER2 protein levels, which differs depending on both the molecular cause of the circadian disruption and the patient's lighting environment. To circumvent such large interindividual variations, we developed an adaptive chronotherapeutics to identify precise dosing regimens that could restore normal circadian phase under different conditions. Our results reveal the importance of photosensitivity in the clinical efficacy of clock-modulating drugs, and enable precision medicine for circadian disruption.
Assuntos
Caseína Quinase Idelta/genética , Relógios Circadianos/genética , Ritmo Circadiano/genética , Transdução de Sinal Luminoso/genética , Proteínas Circadianas Period/genética , Animais , Caseína Quinase Idelta/antagonistas & inibidores , Caseína Quinase Idelta/metabolismo , Relógios Circadianos/efeitos dos fármacos , Relógios Circadianos/efeitos da radiação , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/efeitos da radiação , Criptocromos/genética , Criptocromos/metabolismo , Esquema de Medicação , Cronofarmacoterapia , Regulação da Expressão Gênica , Humanos , Luz , Macaca fascicularis , Camundongos , Proteínas Circadianas Period/metabolismo , Fotoperíodo , Medicina de Precisão , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Especificidade da Espécie , Biologia de Sistemas/métodosRESUMO
The preparation and evaluation of a novel class of CB2 agonists based on a 1,2,3,4-tetrahydropyrrolo[3,4-b]indole moiety are reported. They showed binding affinities up to 4.2 nM toward CB2 with sub-nanomolar EC(50) values. They also showed moderate to good (>350-fold) selectivity over the CB1 receptor.