Agonist and antagonist actions of antipsychotic agents at 5-HT 1A receptors: a [ [formula omitted]]GTPγS binding study

Abstract

Recombinant human (h) 5-HT 1A receptor-mediated G-protein activation was characterised in membranes of transfected Chinese hamster ovary (CHO) cells by use of guanosine-5′- O-(3-[ 35 S ]thio)-triphosphate ([ 35 S ]GTPγS 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 K i values) and high efficacy ( E max>90%, relative to 5-HT=100%). In contrast, ipsapirone, zalospirone and buspirone displayed partial agonist activity. EC 50s for agonist stimulation of [ 35 S ]GTPγS 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 [ 35 S ]GTPγS 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-HT 1A receptors, similar to their affinity at hD 2 dopamine receptors. In contrast, risperidone and sertindole displayed low affinity at h5-HT 1A receptors and behaved as `neutral' antagonists, inhibiting 5-HT-stimulated [ 35 S ]GTPγS binding. Likewise the `typical' neuroleptics, haloperidol, pimozide, raclopride and chlorpromazine exhibited relatively low affinity and `neutral' antagonist activity at h5-HT 1A receptors with K i values which correlated with their respective K b values. The present data show that (i) [ 35 S ]GTPγS binding is an effective method to evaluate the efficacy and potency of agonists and antagonists at recombinant human 5-HT 1A receptors. (ii) Like clozapine, several putatively `atypical' antipsychotic drugs display balanced serotonin h5-HT 1A/dopamine hD 2 receptor affinity and partial agonist activity at h5-HT 1A receptors. (iii) Several `typical' and some putatively `atypical' antipsychotic agents displayed antagonist properties at h5-HT 1A sites with generally much lower affinity than at hD 2 dopamine receptors. It is suggested that agonist activity at 5-HT 1A receptors may be of utility for certain antipsychotic agents.