INTERMEDIATE AFFINITY AND POTENCY OF CLOZAPINE AND LOW-AFFINITY OF OTHER NEUROLEPTICS AND OF ANTIDEPRESSANTS AT H-3 RECEPTORS

It was the aim of the present study to determine the affinities of fou r neuroleptics and five antidepressants for histamine H-3 receptors. I n rat brain cortex membranes, the specifically bound [H-3]-N-alpha-met hylhistamine was monophasically displaced by clozapine (pK(i) 6.15). T he other drugs did not completely displace the radioligand even at 100 mu M; the pK(i) values were: haloperidol (4.91); sulpiride (4.73); am itriptyline (4.56); desipramine (4.15); levomepromazine (4.14); fluovo xamine (4.13); maprotiline (4.09); moclobemide (<4.0). The effect of c lozapine was further examined in a functional H-3 receptor model, i.e. , in superfused mouse brain cortex slices preincubated with [H-3]-nora drenaline. The electrically evoked tritium overflow was not affected b y clozapine 0.5-32 mu M. However, clozapine shifted the concentration- response curve of histamine for its inhibitory effect on the evoked ov erflow to the right, but did not affect the maximum effect of histamin e. The Schild plot yielded a pA(2) value of 6.33. In conclusion, cloza pine shows an intermediate affinity and potency (as a competitive anta gonist) at H-3 receptors. The K-i value of clozapine at H-3 receptors of the classical neuroleptics), but is higher than its K-i values at D -4, 5-HT2 or muscarinic acetylcholine receptors, which according to cu rrent hypotheses, might be involved in the atypical profile of clozapi ne.