科研之友
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摘要
Efavirenz is highly effective at suppressing HIV-1, and the WHO guidelines list it as a component of the first-line antiretroviral (ARV) therapies for treatment-naive patients. Though the pharmacological basis is unclear, efavirenz is commonly associated with a risk for neuropsychiatric adverse events (NPAEs) when taken at the prescribed dose. In many patients these NPAEs appear to subside after several weeks of treatment, though long-term studies show that in some patients the NPAEs persist. In a recent study focusing on the abuse potential of efavirenz, its receptor psychopharmacology was reported to include interactions with a number of established molecular targets for known drugs of abuse, and it displayed a prevailing behavioral profile in rodents resembling an LSD-like activity. In this report, we discovered interactions with additional serotonergic targets that may be associated with efavirenz-induced NPAEs. The most robust interactions were with 5-HT3A and 5-HT6 receptors, with more modest interactions noted for the 5-HT2B receptor and monoamine oxidase A. From a molecular mechanistic perspective, efavirenz acts as a 5-HT6 receptor inverse agonist of Gs-signaling, 5-HT2A and 5-HT2C antagonist of G(q)-signaling, and a blocker of the 5-HT3A receptor currents. Efavirenz also completely or partially blocks agonist stimulation of the M-1 and M-3 muscarinic receptors, respectively. Schild analysis suggests that efavirenz competes for the same site on the 5-HT2A receptor as two known hallucinogenic partial agonists (+/-)-DOI and LSD. Prolonged exposure to efavirenz reduces 5-HT2A receptor density and responsiveness to 5-HT. Other ARVs such as zidovudine, nevirapine and emtricitabine did not share the same complex pharmacological profile as efavirenz, though some of them weakly interact with the 5-HT6 receptor or modestly block GABA(A) currents. Published by Elsevier Ltd.
- 出版日期2016-8
- 单位上海市精神卫生中心
