S-18126 4-(2,3-DIHYDROBENZO[1,4]DIOXIN-6-YL)PIPERAZIN-1-YL METHYL]INDAN-2-YL)), A POTENT, SELECTIVE AND COMPETITIVE ANTAGONIST AT DOPAMINE D-4 RECEPTORS - AN IN-VITRO AND IN-VIVO COMPARISON WITH L-745,870 YL]PIPERAZIN-1-YL)METHYL-1H-PYRROLO[2,3B]PYRIDINE) AND RACLOPRIDE

The novel benzoindane S 18126 possessed > 100-fold higher affinity at cloned, human(h) D-4 (K-l = 2.4 nM) vs. hD(2) (738 nM), hD(3) (2840 nM ), hD(1) (> 3000 nM) and hD(5) (> 3000 nM) receptors and about 50 othe r sites, except sigma(1) receptors (1.6 nM). L 745,870 similarly showe d selectivity for hD(4) (2.5 nM) vs. hD(2) (905 nM) and hD(3) (> 3000 nM) receptors. In contrast, raclopride displayed low affinity at hD(4) (> 3000 nM) vs, hD(2) (1.1 nM) and hD(3) receptors (1.4 nM). Stimulat ion of [S-35]-GTP gamma S binding at hD(4) receptors by dopamine (DA) was blocked by S 18126 and L 745,870 with K-b values of 2.2 and 1.0 nM , respectively, whereas raclopride (> 1000 nM) was inactive. In contra st, raclopride inhibited stimulation of [S-35]-GTP gamma S binding at hD(2) sites by DA with a K-b of 1.4 nM, whereas S 18126 (> 1000 nM) an d L 745,870 (> 1000 nM) were inactive. As concerns presynaptic dopamin ergic receptors, raclopride (0.01-0.05 mg/kg s.c.) markedly enhanced D A synthesis in mesocortical, mesolimbic and nigrostriatal dopaminergic pathways. In contrast, even high doses (2.5-40.0 mg/kg s.c.) of S 181 26 and L 745,870 were only weakly active. Similarly, raclopride (0.016 mg/kg i.v.) abolished inhibition of the firing rate of ventrotegmenta l dopaminergic neurons by apomorphine, whereas even high doses (0.5 mg /kg i.v.) of S 18126 and L 745,870 were only weakly active. As regards postsynaptic dopaminergic receptors, raclopride potently (0.01-0.3 mg /kg s.c.) reduced rotation elicited by quinpirole in rats with unilate ral lesions of the substantia nigra, antagonized induction of hypother mia by PD 128,907, blocked amphetamine-induced hyperlocomotion and was effective in six further models of potential antipsychotic activity. In contrast, S 18126 and L 745,870 were only weakly active in these mo dels (5.0 --> 40.0 mg/kg s.c.). In six models of extrapyramidal and mo tor symptoms, such as induction of catalepsy, raclopride was likewise potently active (0.01-2.0 mg/kg s.c.) whereas S 18126 and L 745,870 we re only weakly active (10.0-80.0 mg/kg s.c.). In freely moving rats, r aclopride (0.16 mg/kg s.c.) increased levels of DA by + 55% in dialysa tes of the frontal cortex. However, it also increased levels of DA in the accumbens and striatum by 70% and 75%, respectively. In contrast t o raclopride, at a dose of 0.16 mg/kg s.c., neither S 18126 nor L 745, 870 modified frontal cortex levels of DA. However, at a high dose (40. 0 mg/kg s.c.), S 18126 increased dialysate levels of DA (+ 85%) and no radrenaline (+ 100%), but not serotonin (+ 10%), in frontal cortex wit hout affecting DA levels in accumbens (+ 10%) and striatum (+ 10%). In conclusion, S 18126 and L 745,870 behave as potent and selective anta gonists of cloned, hD(4) vs. other dopaminergic receptor types in vitr o. However, their in vivo effects at high doses probably reflect resid ual antagonist actions at D-2 (or D-3) receptors. Selective blockade o f D-4 receptors was thus associated neither with a modification of dop aminergic transmission nor with antipsychotic (antiproductive) or extr apyramidal properties. The functional effects of selective D-4 recepto r blockade remain to be established.