RESUMEN
Buprenorphine (0.3-3.0 mg/kg) produced dose-dependent protection against the lethal effects of cocaine in mice. The (+)-enantiomer of buprenorphine did not protect up to doses over 100 times greater than the lowest effective dose of its (-)-enantiomer. The protective effects were also produced by the opioid agonists morphine and methadone, but not by the opioid antagonist, naltrexone. Low doses of naltrexone (0.3-1.0 mg/kg) blocked the protective effects of buprenorphine. Protection conferred by buprenorphine was not observed in CXBK mice, a recombinant inbred strain relatively devoid of mu-opioid receptors. Thus, buprenorphine appears to protect against the lethal effects of cocaine by a process mediated by mu-opioid receptors. The present results should provide some additional safety assurance in future clinical trials with buprenorphine, especially in outpatient trials where cocaine abuse may continue along with treatment.
Asunto(s)
Buprenorfina/farmacología , Cocaína/toxicidad , Animales , Encéfalo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Metadona/farmacología , Ratones , Ratones Endogámicos , Morfina/farmacología , Naltrexona/farmacología , Receptores Opioides/efectos de los fármacos , Receptores Opioides mu , Convulsiones/inducido químicamente , Convulsiones/prevención & controlRESUMEN
Adenosine 5'-alkylphosphates are potent inhibitors of acetyl- and acyl-CoA synthetase. In each case, the most effective inhibitor in the series is homologous with the tightly bound acyl adenylate intermediate. Adenosine 5'-ethylphosphate (Ki = 33 nM) is 88-fold more potent than adenosine 5'-methylphosphate (Ki = 2900 nM) as a competitive inhibitor of acetyl-CoA synthetase; the contribution of a single carbon to the observed binding energy (-11 kJ/mol) is much larger than is typically observed.
