Newman-Tancredi A, Gavaudan S, Conte C, Chaput C, Touzard M, Verrièle L, Audinot V, Millan M J
Department of Psychopharmacology, Institut de Recherches Servier, Paris, France.
Eur J Pharmacol. 1998 Aug 21;355(2-3):245-56. doi: 10.1016/s0014-2999(98)00483-x.
Recombinant human (h) 5-HT1A receptor-mediated G-protein activation was characterised in membranes of transfected Chinese hamster ovary (CHO) cells by use of guanosine-5'-O-(3-[35S]thio)-triphosphate ([35S]GTPgammaS binding). The potency and efficacy of 21 5-HT receptor agonists and antagonists was determined. The agonists, 5-CT (carboxamidotryptamine) and flesinoxan displayed high affinity (subnanomolar Ki values) and high efficacy (Emax > 90%, relative to 5-HT = 100%). In contrast, ipsapirone, zalospirone and buspirone displayed partial agonist activity. EC50s for agonist stimulation of [35S]GTPgammaS binding correlated well with Ki values from competition binding (r = +0.99). Among the compounds tested for antagonist activity, methiothepin and (+)butaclamol exhibited 'inverse agonist' behaviour, inhibiting basal [35S]GTPgammaS binding. The actions of 17 antipsychotic agents were investigated. Clozapine and several putatively 'atypical' antipsychotic agents, including ziprasidone, quetiapine and tiospirone, exhibited partial agonist activity and marked affinity at h5-HT1A receptors, similar to their affinity at hD2 dopamine receptors. In contrast, risperidone and sertindole displayed low affinity at h5-HT1A receptors and behaved as 'neutral' antagonists, inhibiting 5-HT-stimulated [35S]GTPgammaS binding. Likewise the 'typical' neuroleptics, haloperidol, pimozide, raclopride and chlorpromazine exhibited relatively low affinity and 'neutral' antagonist activity at h5-HT1A receptors with Ki values which correlated with their respective Kb values. The present data show that (i) [35S]GTPgammaS binding is an effective method to evaluate the efficacy and potency of agonists and antagonists at recombinant human 5-HT1A receptors. (ii) Like clozapine, several putatively 'atypical' antipsychotic drugs display balanced serotonin h5-HT1A/dopamine hD2 receptor affinity and partial agonist activity at h5-HT1A receptors. (iii) Several 'typical' and some putatively 'atypical' antipsychotic agents displayed antagonist properties at h5-HT1A sites with generally much lower affinity than at hD2 dopamine receptors. It is suggested that agonist activity at 5-HT1A receptors may be of utility for certain antipsychotic agents.
通过使用鸟苷-5'-O-(3-[35S]硫代)-三磷酸([35S]GTPγS结合)，在转染的中国仓鼠卵巢(CHO)细胞膜中对重组人(h)5-HT1A受体介导的G蛋白激活进行了表征。测定了21种5-HT受体激动剂和拮抗剂的效力和效能。激动剂5-CT(羧酰胺色胺)和氟司必林表现出高亲和力(亚纳摩尔Ki值)和高效能(相对于5-HT = 100%，Emax>90%)。相比之下，伊沙匹隆、扎螺普隆和丁螺环酮表现出部分激动剂活性。激动剂刺激[35S]GTPγS结合的EC50与竞争结合的Ki值相关性良好(r = +0.99)。在测试拮抗剂活性的化合物中，甲硫哒嗪和(+)丁酰苯表现出“反向激动剂”行为，抑制基础[35S]GTPγS结合。研究了17种抗精神病药物的作用。氯氮平和几种被认为是“非典型”的抗精神病药物，包括齐拉西酮、喹硫平和替螺环酮，表现出部分激动剂活性和对h5-HT1A受体的显著亲和力，类似于它们对hD2多巴胺受体的亲和力。相比之下，利培酮和舍吲哚对h5-HT1A受体表现出低亲和力，并表现为“中性”拮抗剂，抑制5-HT刺激的[35S]GTPγS结合。同样，“典型”抗精神病药物氟哌啶醇、匹莫齐特、雷氯必利和氯丙嗪在h5-HT1A受体上表现出相对较低的亲和力和“中性”拮抗剂活性，其Ki值与各自的Kb值相关。目前的数据表明：(i)[35S]GTPγS结合是评估激动剂和拮抗剂对重组人5-HT1A受体的效能和效力的有效方法。(ii)与氯氮平一样，几种被认为是“非典型”的抗精神病药物在h5-HT1A受体上表现出平衡的5-羟色胺h5-HT1A/多巴胺hD2受体亲和力和部分激动剂活性。(iii)几种“典型”和一些被认为是“非典型”的抗精神病药物在h5-HT1A位点表现出拮抗剂特性，其亲和力通常远低于对hD2多巴胺受体的亲和力。有人提出，5-HT1A受体的激动剂活性可能对某些抗精神病药物有用。
