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The novel benzopyranopyrrolidine and potential antipsychotic, S16924 ((+)-2-{1-[2-(2,3-dihydro-benzo[1,4] dioxin-5-yloxy)-ethyl]-pyrrolidin-3yl}-1-(4-fluoro-phenyl)-ethanone), displays marked affinity for serotonin (5-HT)1A, 5-HT2A and dopamine D2 receptors. Herein, we show that it also possesses high affinity for the cloned, INI isoform of h5-HT2C receptors (pKi=8.28) stably expressed in CHO cells. Similarly, clozapine (8.04) was a potent ligand, whereas haloperidol (<6.0) showed low affinity. As demonstrated by fura2-detection, S16924 concentration-dependently abolished (pKb=7.93) the 5-HT-induced elevation in intracellular levels of Ca2+ ([Ca2+]i) in a CHO cell line stably expressing the INI isoform of 5-HT2C receptors. Further, as determined by depletion of membrane-bound levels of pre-labelled [3H]phosphatidylinositols ([3H]PI), S16924 concentration-dependently, surmountably and competitively blocked the activation of phospholipase C by 5-HT. This action was expressed with a pA2 of 7.89 according to Schild analysis. Clozapine likewise inhibited 5-HT-induced alterations in [Ca2+]i and [3H]PI levels with pKbs of 7.43 and 7.84, respectively, whereas haloperidol was inactive (<5.0 in each case). Applied alone, S16924, clozapine and haloperidol modified levels of neither [Ca2+]i nor [3H]PI. In conclusion, in analogy to clozapine, and in contrast to haloperidol, S16924 behaves as a potent and competitive antagonist at h5-HT2C receptors, the blockade of which may contribute to its distinctive functional profile of activity. [ABSTRACT FROM AUTHOR]

Abstract: Cloned, human dopamine D1 receptors recruit multiple effectors but the G-protein subtype(s) activated by cerebral populations remain poorly defined, a question addressed using a rapid immunocapture technique. In rat striatum, dopamine (DA) and four selective, benzazepine agonists at D1 receptors concentration-dependently enhanced [35S]GTPγS binding to Gαs/olf. For all drugs, Gαq was also recruited with similar potencies and efficacies. Comparable observations were made in the cortex wherein profiles of Gαs/olf vs Gαq activation were also highly correlated. In contrast to Gαs/olf and Gαq, Gαo and Gαi were activated neither in the striatum nor in the cortex, except for SKF82958. As compared to DA, both SKF81297 and SKF82958 were full agonists at Gs/olf and Gq in cortex and striatum, whereas SKF38393 behaved as a partial agonist. Likewise, the “atypical” agonist, SKF83959 only partially activated Gαq and also Gs/olf in these two regions. In both striatum and cortex, the selective D1 receptor antagonist, SCH23390, abolished the recruitment of Gαq and Gαs by DA, and the action of DA was partially attenuated by SKF83959. These findings demonstrate that, in native CNS tissue, DA and other D1 receptor agonists activate Gαs and Gαq with similar potencies and efficacies, suggesting their recruitment via pharmacologically-indistinguishable populations of D1 receptors, and show that SPA technology is well-adapted to study the coupling of native DA receptors. [Copyright &y& Elsevier]

To date, the lack of highly selective antagonists at the dopamine D3 receptor has hampered clarification of their involvement in the actions of currently used therapies in Parkinson''s disease. However, the novel benzopyranopyrrole, S33084, displays greater than 100-fold selectivity as an antagonist for D3 versus D2 receptors and all other sites tested. S33084 was administered to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets previously primed with levodopa to elicit dyskinesia. Administered alone, S33084 exerted a modest, but significant, anti-parkinsonian effect without provoking dyskinesia. At low D3-selective doses (0.16 and 0.64 mg/kg), S33084 potentiated, though to different extents and in qualitatively different ways, the anti-parkinsonian actions of both ropinirole and levodopa. At these doses, S33084 did not significantly modify levodopa-induced or ropinirole-induced dyskinesia. These data suggest that ropinirole and levodopa do not exert their anti-parkinsonian or pro-dyskinetic actions via D3 receptor stimulation. Indeed, stimulation of D3 receptors may be detrimental to the anti-parkinsonian properties of D2/D3 agonists. Selectivity for stimulation of D2, over D3, receptors may therefore be a beneficial property of dopamine receptor agonists in management of motor symptoms of Parkinson''s disease patients with established dyskinesia. [Copyright &y& Elsevier]