Dopamine receptors belong to the family of G protein-coupled receptors. On the basis of the homology between these receptors, three different dopamine receptors (D1, D2, D3) have been cloned. Dopamine receptors are primary targets for drugs used in the treatment of psychomotor disorders such as Parkinson's disease and schizophrenia. In the management of socially withdrawn and treatment-resistant schizophrenics, clozapine is one of the most favoured antipsychotics because it does not cause tardive dyskinesia. Clozapine, however, has dissociation constants for binding to D2 and D3 that are 4 to 30 times the therapeutic free concentration of clozapine in plasma water. This observation suggests the existence of other types of dopamine receptors which are more sensitive to clozapine. Here we report the cloning of a gene that encodes such a receptor (D4). The D4 receptor gene has high homology to the human dopamine D2 and D3 receptor genes. The pharmacological characteristics of this receptor resembles that of the D2 and D3 receptors, but its affinity for clozapine is one order of magnitude higher. Recognition and characterization of this clozapine neuroleptic site may prove useful in the design of new types of drugs.

The affinities of olanzapine, clozapine, haloperidol, and four potential antipsychotics were compared on binding to the neuronal receptors of a number of neurotransmitters. In both rat tissues and cell lines transfected with human receptors olanzapine had high affinity for dopamine D1, D2, D4, serotonin (5HT)2A, 5HT2C, 5HT3, alpha 1-adrenergic, histamine H1, and five muscarinic receptor subtypes. Olanzapine had lower affinity for alpha 2-adrenergic receptors and relatively low affinity for 5HT1 subtypes, GABAA, beta-adrenergic receptors, and benzodiazepine binding sites. The receptor binding affinities for olanzapine was quite similar in tissues from rat and human brain. The binding profile of olanzapine was comparable to the atypical antipsychotic clozapine, while the binding profiles for haloperidol, resperidone, remoxipride, Org 5222, and seroquel were substantially different from that of clozapine. The receptor binding profile of olanzapine is consistent with the antidopaminergic, antiserotonergic, and antimuscarinic activity observed in animal models and predicts atypical antipsychotic activity in man.

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The authors propose that fast dissociation from the D(2) receptor makes an antipsychotic more accommodating of physiological dopamine transmission, permitting an antipsychotic effect without motor side effects, prolactin elevation, or secondary negative symptoms. In contrast to the multireceptor hypotheses, the authors predict that the atypical antipsychotic effect can be produced by appropriate modulation of the D(2) receptor alone; the blockade of other receptors is neither necessary nor sufficient.

Back ground: Al though the prin ci pal brain tar get that all an tipsy chotic drugs at tach to is the do pamine D 2 re cep tor, tra di tional or typi cal an tipsy chot ics, by at tach ing to it, in duce ex tra py r a mi dal signs and symp toms (EPS). They also, by bind ing to the D2 re cep tor, ele vate se rum pro lac tin. Atypi cal antipsy chot ics given in dos ages within the clini cally ef fec tive range do not bring about these ad verse clini cal ef fects. To un der stand how these drugs work, it is im por tant to ex am ine the atypi cal an tipsychot ics' mecha nism of ac tion and how it dif fers from that of the more typi cal drugs. Method: This re view analy zes the af fini ties, the oc cu pan cies, and the dis so cia tion time-course of vari ous an tipsy chot ics at do pa mine D 2 re cep tors and at se ro tonin (5-HT) re cep tors, both in the test tube and in live pa tients. Re sults: Of the 31 an tipsy chot ics ex am ined, the older tra di tional an tipsy chot ics such as tri flu perazine, pi mozide, chlor pro maz ine, fluphe nazine, ha loperi dol, and flupen thixol bind more tightly than do pa mine it self to the do pa mine D 2 re cep tor, with dis so cia tion con stants that are lower than that for do pa mine. The newer, atypi cal an tipsy chot ics such as queti apine, re moxi pride, clo zap ine, ol anzap ine, sert in dole, zi pra si done, and amisul pride all bind more loosely than do pa mine to the do pamine D 2 re cep tor and have dis so cia tion con stants higher than that for do pa mine. These tight and loose bind ing data agree with the rates of an tipsy chotic dis so cia tion from the human-cloned D 2 recep tor. For in stance, ra dio ac tive ha loperi dol, chlor pro maz ine, and ra clo pride all dis s o ci ate very slowly over a 30-minute time span, while ra dio ac tive queti apine, clo zap ine, re moxi pride, and amisul pride dis so ci ate rap idly, in less than 60 sec onds. These data also match clini cal brainimaging find ings that show ha loperi dol re main ing con stantly bound to D2 in hu mans un der go ing 2 posi tron emis sion to mo gra phy (PET) scans 24 hours apart. Con versely, the oc cu pa tion of D 2 by clo zap ine or queti apine has mostly dis ap peared af ter 24 hours. Con clu sion: Atypi cals clini cally help pa tients by tran siently oc cu py ing D 2 re cep tors and then rap idly dis so ci at ing to al low nor mal do pa mine neu ro trans mis sion. This keeps pro lac tin lev els nor mal, spares cog ni tion, and ob vi ates EPS. One the ory of atypi cal ity is that the newer drugs block 5-HT 2A re ceptors at the same time as they block do pa mine re cep tors and that, some how, this serotonin-dopamine bal ance con fers atypi cal ity. This, how ever, is not borne out by the re sults. While 5-HT 2A re cep tors are read ily blocked at low dos ages of most atypi cal an tipsy chotic drugs (with the im por tant ex ceptions of re moxi pride and amisul pride, nei ther of which is avail able for use in Can ada) the do s ages at which this hap pens are be low those needed to al le vi ate psy ...