(+)-UH 232 maleate

Evidence that antipsychotic drugs are inverse agonists at D2 dopamine receptors.[Pubmed:9208141]

Br J Pharmacol. 1997 Jun;121(4):731-6.

1. The effects of a number of D2-like dopamine receptor antagonists have been determined on forskolin-stimulated cyclic AMP accumulation in Chinese hamster ovary (CHO) cells expressing the human D2short dopamine receptor (CHO-D2S cells). 2. Dopamine inhibited the effect of forskolin (as expected for a D2 receptor). However, all of the antagonists tested, apart from UH232 and (-)-butaclamol, were able to increase cyclic AMP accumulation above the forskolin control level. (+)-Butaclamol elicited a similar stimulation of forskolin-stimulated cyclic AMP accumulation in a CHO cell line expressing human D2long dopamine receptors whereas it exhibited no stimulating effect on forskolin-stimulated cyclic AMP accumulation in untransfected CHO-K1 cells. 3. There was a strong correlation between the EC50 values of these compounds for potentiation of cyclic AMP accumulation and their Ki values from radioligand binding experiments in CHO-D2S cells. 4. The effects of both (+)-butaclamol and dopamine in CHO-D2S cells were inhibited by pre-treatment with pertussis toxin indicating a role for Gi/Go proteins. 5. UH232 did not significantly affect forskolin-stimulated cyclic AMP accumulation but this substance was able to inhibit the effects of both dopamine and (+)-butaclamol in a concentration-dependent manner. Thus the effects of (+)-butaclamol on forskolin-stimulated cyclic AMP accumulation are mediated directly via the D2 receptor rather than by reversal of the effects of an endogenous agonist. 6. These data suggest that the D2 dopamine receptor antagonists tested here, many of which are used clinically as antipsychotic drugs, are in fact inverse agonists at human D2 dopamine receptors.

The preferential dopamine D3 receptor ligand, (+)-UH232, is a partial agonist.[Pubmed:7498261]

Eur J Pharmacol. 1995 Aug 25;282(1-3):R3-4.

In a NG 108 15 hybrid cell line stably expressing a recombinant dopamine D3 receptor, (+)-UH 232 (cis-(+)-1S,2R)-5-methoxy-1-methyl-2-(di-n- propylamino)tetralin), a partially selective D3 receptor ligand, stimulates mitogenesis, as measured by incorporation of [3H]thymidine, with an EC50 of 7.6 nM and a maximal increase corresponding to 23% of the response elicited by quinpirole, a full agonist. This effect was antagonised by nafadotride, a D3 receptor-selective antagonist. (+)-UH 232 also antagonised quinpirole-induced mitogenesis with a Ki value of 9.4 nM. (+)-UH 232 (1 microM) inhibited by 22% the forskolin-induced accumulation of cAMP, whilst the inhibition by quinpirole (100 nM) was 53%. These results indicate that (+)-UH 232 is a partial agonist at the D3 receptor with an intrinsic activity of 0.2-0.4.

(+)-AJ 76 and (+)-UH 232: central stimulants acting as preferential dopamine autoreceptor antagonists.[Pubmed:2880302]

Naunyn Schmiedebergs Arch Pharmacol. 1986 Nov;334(3):234-45.

The biochemical and behavioral effects of the putative dopamine autoreceptor antagonists cis-(+)-5-methoxy-1-methyl-2-(n-propylamino)tetralin, (+)-AJ 76 and cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin, (+)-UH 232, were evaluated in various in vivo models in rats. Both compounds produced a marked elevation in brain dopamine synthesis and turnover with only slight effects on the synthesis and turnover of serotonin (5-HT) and noradrenaline being noted. (+)-AJ 76 and (+)-UH 232 also failed to antagonize the decrease in cortical noradrenaline synthesis rate caused by the alpha 2 agonist clonidine. The apomorphine-induced decrease in dopamine synthesis rate in gamma-butyrolactone (GBL) treated animals was completely blocked by (+)-AJ 76 and (+)-UH 232 but not by d-amphetamine or methylphenidate. In activity experiments using habituated animals, (+)-AJ 76 and (+)-UH 232 produced locomotor stimulation and weak stereotypies and antagonized the sedative effects of low doses of apomorphine. Locomotor hyperactivity induced by apomorphine or the dopamine agonist DiPr-5,6-ADTN was antagonized by (+)-UH 232 and to a lesser degree by (+)-AJ 76. The locomotor hyperactivity produced by (+)-AJ 76, (+)-UH 232 and methylphenidate was completely prevented by reserpine pretreatment and partially blocked by the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (alpha-MT), whereas d-amphetamine-induced hyperactivity was only antagonized by alpha-MT pretreatment. It is concluded that (+)-AJ 76 and (+)-UH 232 produce behavioral stimulation via a preferential antagonism on central dopamine autoreceptors, an action different from that of all known stimulants including apomorphine, d-amphetamine and methylphenidate. (+)-AJ 76 and (+)-UH 232 possess but weak antagonistic effects on postsynaptic dopamine receptors and only the latter compound is able to induce sedation in rats.

Novel dopamine receptor agonists and antagonists with preferential action on autoreceptors.[Pubmed:3927002]

J Med Chem. 1985 Aug;28(8):1049-53.

The enantiomers of cis-5-hydroxy-1-methyl-2-(di-n-propylamino)tetralin and its methyl ether have been synthesized. The compounds were tested for central dopamine (DA) receptor activity, by using biochemical and behavioral tests in rats. The (1R,2S)-(-) enantiomers of 1 and 2 are characterized as centrally acting DA-receptor agonists while the corresponding (1S,2R)-(+) enantiomers are characterized as centrally acting DA-receptor antagonists. Compounds (+)-1 and (+)-2 differ from classical neuroleptics in being able to increase DA synthesis rate in a wide dose range without reducing locomotor activity, suggesting a pronounced selectivity for DA autoreceptors. Also the (-) enantiomers seem to act preferentially on DA autoreceptors.