Grim T W, Morales A J, Thomas B F, Wiley J L, Endres G W, Negus S S, Lichtman A H
Department of Pharmacology, Virginia Commonwealth University, Richmond, Virginia (T.W.G., A.J.M., S.S.N., A.H.L.); RTI International, Research Triangle Park, North Carolina (B.F.T., J.L.W.); and PinPoint Testing, LLC, AR (G.W.E.)
Department of Pharmacology, Virginia Commonwealth University, Richmond, Virginia (T.W.G., A.J.M., S.S.N., A.H.L.); RTI International, Research Triangle Park, North Carolina (B.F.T., J.L.W.); and PinPoint Testing, LLC, AR (G.W.E.).
J Pharmacol Exp Ther. 2017 Jul;362(1):210-218. doi: 10.1124/jpet.117.240192. Epub 2017 Apr 25.
Synthetic cannabinoids (SCs) represent an emerging class of abused drugs associated with psychiatric complications and other substantial health risks. These ligands are largely sold over the internet for human consumption, presumably because of their high cannabinoid 1 receptor (CBR) affinity and their potency in eliciting pharmacological effects similar to Δ-tetrahydrocannabinol (THC), as well as circumventing laws illegalizing this plant. Factors potentially contributing to the increased prevalence of SC abuse and related hospitalizations, such as increased CBR efficacy and non-CBR targets, highlight the need for quantitative pharmacological analyses to determine receptor mediation of the pharmacological effects of cannabinoids. Accordingly, the present study used pA and pK analyses for quantitative determination of CBR mediation in which we utilized the CBR-selective inverse agonist/antagonist rimonabant to elicit rightward shifts in the dose-response curves of five SCs (i.e., A-834,735D; WIN55,212-2; CP55,950; JWH-073; and CP47,497) and THC in producing common cannabimimetic effects (i.e., catalepsy, antinociception, and hypothermia). The results revealed overall similarity of pA and pK values for these compounds and suggest that CBRs, and not other pharmacological targets, largely mediated the central pharmacological effects of SCs. More generally, affinity estimation offers a powerful pharmacological approach to assess potential receptor heterogeneity subserving in vivo pharmacological effects of SCs.
合成大麻素（SCs）是一类新出现的滥用药物，与精神并发症及其他重大健康风险相关。这些配体大多通过互联网销售以供人使用，推测原因是它们对大麻素1受体（CBR）具有高亲和力，且在引发类似于Δ-四氢大麻酚（THC）的药理作用方面效力较强，同时还规避了将这种植物定为非法的法律。可能导致合成大麻素滥用及相关住院率上升的因素，如CBR效力增加和非CBR靶点，凸显了进行定量药理学分析以确定大麻素药理作用的受体介导作用的必要性。因此，本研究采用pA和pK分析来定量测定CBR介导作用，其中我们利用CBR选择性反向激动剂/拮抗剂利莫那班使五种合成大麻素（即A-834,735D；WIN55,212-2；CP55,950；JWH-073；和CP47,497）以及THC产生常见大麻模拟效应（即僵住症、抗伤害感受和体温过低）的剂量反应曲线向右移动。结果揭示了这些化合物pA和pK值的总体相似性，并表明主要是CBR而非其他药理靶点介导了合成大麻素的中枢药理作用。更一般地说，亲和力估计为评估合成大麻素体内药理作用的潜在受体异质性提供了一种强大的药理学方法。
