Lever John R, Miller Dennis K, Fergason-Cantrell Emily A, Green Caroline L, Watkinson Lisa D, Carmack Terry L, Lever Susan Z
Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri (J.R.L., E.A.F.-C., L.D.W., T.L.C.); and Department of Radiology and Radiopharmaceutical Sciences Institute (J.R.L., E.A.F.-C., L.D.W., T.L.C.), Department of Medical Pharmacology and Physiology (J.R.L.), Department of Psychological Sciences (D.K.M., C.L.G.), Center for Translational Neuroscience (D.K.M.), Department of Chemistry (S.Z.L.), and MU Research Reactor Center (S.Z.L.), University of Missouri, Columbia, Missouri
Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri (J.R.L., E.A.F.-C., L.D.W., T.L.C.); and Department of Radiology and Radiopharmaceutical Sciences Institute (J.R.L., E.A.F.-C., L.D.W., T.L.C.), Department of Medical Pharmacology and Physiology (J.R.L.), Department of Psychological Sciences (D.K.M., C.L.G.), Center for Translational Neuroscience (D.K.M.), Department of Chemistry (S.Z.L.), and MU Research Reactor Center (S.Z.L.), University of Missouri, Columbia, Missouri.
J Pharmacol Exp Ther. 2014 Oct;351(1):153-63. doi: 10.1124/jpet.114.216671. Epub 2014 Aug 6.
Psychostimulant effects of cocaine are mediated partly by agonist actions at sigma-1 (σ1) receptors. Selective σ1 receptor antagonists attenuate these effects and provide a potential avenue for pharmacotherapy. However, the selective and high affinity σ1 antagonist PD144418 (1,2,3,6-tetrahydro-5-[3-(4-methylphenyl)-5-isoxazolyl]-1-propylpyridine) has been reported not to inhibit cocaine-induced hyperactivity. To address this apparent paradox, we evaluated aspects of PD144418 binding in vitro, investigated σ1 receptor and dopamine transporter (DAT) occupancy in vivo, and re-examined effects on locomotor activity. PD144418 displayed high affinity for σ1 sites (Ki 0.46 nM) and 3596-fold selectivity over σ2 sites (Ki 1654 nM) in guinea pig brain membranes. No appreciable affinity was noted for serotonin and norepinephrine transporters (Ki >100 μM), and the DAT interaction was weak (Ki 9.0 μM). In vivo, PD144418 bound to central and peripheral σ1 sites in mouse, with an ED50 of 0.22 μmol/kg in whole brain. No DAT occupancy by PD144418 (10.0 μmol/kg) or possible metabolites were observed. At doses that did not affect basal locomotor activity, PD144418 (1, 3.16, and 10 μmol/kg) attenuated cocaine-induced hyperactivity in a dose-dependent manner in mice. There was good correlation (r(2) = 0.88) of hyperactivity reduction with increasing cerebral σ1 receptor occupancy. The behavioral ED50 of 0.79 μmol/kg corresponded to 80% occupancy. Significant σ1 receptor occupancy and the ability to mitigate cocaine's motor stimulatory effects were observed for 16 hours after a single 10.0 μmol/kg dose of PD144418.
可卡因的精神兴奋作用部分是由其对σ1受体的激动作用介导的。选择性σ1受体拮抗剂可减弱这些作用，并为药物治疗提供了一条潜在途径。然而，据报道，选择性高亲和力σ1拮抗剂PD144418（1,2,3,6-四氢-5-[3-(4-甲基苯基)-5-异恶唑基]-1-丙基吡啶）并不能抑制可卡因诱导的多动。为了解决这一明显的矛盾，我们评估了PD144418体外结合的相关方面，研究了体内σ1受体和多巴胺转运体（DAT）的占有率，并重新审视了其对运动活性的影响。在豚鼠脑膜中，PD144418对σ1位点表现出高亲和力（Ki 0.46 nM），对σ2位点的选择性为3596倍（Ki 1654 nM）。对5-羟色胺和去甲肾上腺素转运体未观察到明显亲和力（Ki>100μM），与DAT的相互作用较弱（Ki 9.0μM）。在体内，PD144418与小鼠中枢和外周的σ1位点结合，全脑的ED50为0.22μmol/kg。未观察到PD144418（10.0μmol/kg）或其可能的代谢产物对DAT的占有率。在不影响基础运动活性的剂量下，PD144418（1、3.16和10μmol/kg）在小鼠中以剂量依赖性方式减弱可卡因诱导的多动。多动减少与脑内σ1受体占有率增加之间存在良好的相关性（r(2)=0.88）。行为ED50为0.79μmol/kg，对应于80%的占有率。单次给予10.0μmol/kg剂量的PD144418后16小时，观察到显著的σ1受体占有率以及减轻可卡因运动刺激作用的能力。
