AGONIST AND ANTAGONIST ACTIONS OF ANTIPSYCHOTIC AGENTS AT 5-HT1A RECEPTORS - A [S-35] GTP-GAMMA-S BINDING STUDY

Recombinant human (h) 5-HT1A receptor-mediated G-protein activation wa s characterised in membranes of transfected Chinese hamster ovary (CHO ) cells by use of guanosine-5'-O-(3-[S-35]thio)-triphosphate ([S-35]GT P gamma S binding). The potency and efficacy of 21 5-HT receptor agoni sts and antagonists was determined. The agonists, 5-CT (carboxamidotry ptamine) and flesinoxan displayed high affinity (subnanomolar K-i valu es) and high efficacy (E-max > 90%, relative to 5-HT = 100%). In contr ast, ipsapirone, zalospirone and buspirone displayed partial agonist a ctivity. EC(50)s for agonist stimulation of [S-35]GTP gamma S binding correlated well with K-i values from competition binding (r = +0.99). Among the compounds tested for antagonist activity, methiothepin and ( +)butaclamol exhibited 'inverse agonist' behaviour, inhibiting basal [ S-35]GTP gamma S binding. The actions of 17 antipsychotic agents were investigated. Clozapine and several putatively 'atypical' antipsychoti c agents, including ziprasidone, quetiapine and tiospirone, exhibited partial agonist activity and marked affinity at h5-HT1A receptors, sim ilar to their affinity at hD(2) dopamine receptors. In contrast, rispe ridone and sertindole displayed low affinity at h5-HT1A receptors and behaved as 'neutral' antagonists, inhibiting 5-HT-stimulated [S-35]GTP gamma S binding. Likewise the 'typical' neuroleptics, haloperidol, pi mozide, raclopride and chlorpromazine exhibited relatively low affinit y and 'neutral' antagonist activity at h5-HT1A receptors with K-i valu es which correlated with their respective K-i values. The present data show that (i) [S-35]GTP gamma S binding is an effective method to eva luate the efficacy and potency of agonists and antagonists at recombin ant human 5-HT1A receptors. (ii) Like clozapine, several putatively 'a typical' antipsychotic drugs display balanced serotonin h5-HT1A/dopami ne hD(2) receptor affinity and partial agonist activity at hS-HT1A rec eptors. (iii) Several 'typical' and some putatively 'atypical' antipsy chotic agents displayed antagonist properties at h5-HT1A sites with ge nerally much lower affinity than at hD(2) dopamine receptors. It is su ggested that agonist activity at 5-HT1A receptors may be of utility fo r certain antipsychotic agents. (C) 1998 Elsevier Science B.V. All rig hts reserved.