D2 Receptor Sites Research Articles

Clinical importance of D-1 and D-2 receptors.

The existence of subtypes of dopamine receptors as defined by Kebabian and Calne is now well accepted. The D1 receptor is typically associated with stimulation of adenylate cyclase, while the D2 receptor is either independent of adenylate cyclase or mediates its inhibition. Considerable interest has been generated by the potential physiological and clinical roles of these receptor subtypes. Availability of agonists and antagonists specifically acting at the D1 or D2 receptor site has stimulated research to characterize the functional effects of each receptor subtype. This might facilitate the development of effective compounds to control the signs and symptoms of Parkinson's disease and perhaps prevent the induction of debilitating side effects. Recent evidence indicates that D1 receptor stimulation is required to obtain full expression of the D2 receptor site, which has typically been associated with the clinical benefits of dopaminergic therapy. Both pre- and postsynaptic location of the receptors must also be taken into consideration as well as involvement of other neuronal systems. It appears that in PD, progressive involvement of the dopaminergic pathways is the principal pathological course, however, noradrenergic and serotonergic pathways are likewise involved. This multineuronal involvement suggests that drugs acting specifically at receptor sites, located on both pre- and postsynaptic neurons, might be required at different times during the course of the disease process to control its symptoms and/or the complications occurring after long-term treatment with a given drug.

Psychotropic agents: synthesis and antipsychotic activity of substituted .beta.-carbolines

A series of novel substituted beta-carbolines was synthesized and tested for potential antipsychotic activity. Several compounds displayed moderate antipsychotic activity in vitro and in vivo as determined by relevant receptor binding assays and behavioral tests. The effect of substituents on antipsychotic activity was examined. The beta-carbolines 10 and 19 containing 2-(2-pyridinyl)ethyl and 2-(2-quinolinyl)ethyl side chains were the most potent analogues, blocking discrete trial conditioned avoidance responding in rats with AB50's of 23 and 10 mg/kg, respectively. Both showed moderate activity at the D2 receptor sites, but they lacked oral activity. In contrast, the beta-carboline 13 containing the 4-(4-pyridinyl)butyl side chain exhibited oral activity in the discrete trial conditioned avoidance screen with an AB50 of 31 mg/kg. Most compounds did not antagonize apomorphine-induced stereotyped behavior, which is indicative of low potential for extrapyramidal side effect (EPS) liability.

Functional interactive effects of D1 and D2 dopamine receptor blockade.

Multiple types of dopamine (DA) receptors have been shown to exist in the striatum (Seeman, 1980). These receptor populations have been divided into those which stimulate the enzyme adenylate cyclase (D2 sites) and those which are not directly linked to or suppress this enzyme (D2 sites, Kebabian and Calne, 1978; Stoof and Kebabian, 1984). Until now, the functional effects of DA receptor activation in the brain have been attributed to drug action at D2 receptor sites. Thus, good correlations exist between the ability of neuroleptic drugs to displace 3H-spiroperidol from specific binding sites on D2 receptors (Seeman, 1980) and their antipsychotic activity (Seeman, 1977; Creese et al., 1979; Seeman, 1980). Although no obvious physiological function for D1 sites in brain is known, recent evidence has suggested an interaction between D1 and D2 sites. For example, SKF 38393, a D1 agonist, stimulates the efflux of cAMP from superfused striatal tissue slices, and this stimulation is antagonized by LY 141865, a selective D2 agonist.KeywordsAdenylate CyclaseReceptor BlockadeThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Evidence that apomorphine and pergolide induce rotation in rats by different actions on D1 and D2 receptor sites

Apomorphine and the ergot derivative pergolide induced dose-dependent contralateral rotation in rats with unilateral 6-hydroxydopamine denervation of the ascending dopamine pathways. This was interpreted as an action on supersensitive receptors. However, large differences were found when comparing apomorphine and pergolide dose-response curves as well as the patterns of rotational behaviour the compounds elicited. Pergolide had a steep dose-response curve, while apomorphine had a flatter curve reaching a plateau at the dose of 1 mg/kg s.c. In doses higher than 1 mg/kg, apomorphine induced self-mutilation, while this was infrequent after pergolide. Apomorphine induced a two-peak pattern of rotation that never occured when the same rats were tested with the ergot derivative. Both drugs induced dose-dependent ipsilateral rotation in animals with unilateral striatal kainic acid lesions but at doses 100 times higher. This effect was interpreted as an action on normosensitive receptors situated on the intact side. The differences between apomorphine and pergolide may be explained in terms of actions on different dopamine receptors, since the agonists were differently inhibited by neuroleptics acting on D1- or D2-type receptors. The D1/D2 antagonist cis-flupenthixol blocked both apomorphine and pergolide with similar potency, while sulpiride, a substituted benzamine devoid of any effect on D1 receptors, was a poor inhibitor of the apomorphine response. In contrast, sulpiride blocked pergolide rotation at doses 1000 times lower than those needed to block apomorphine rotation. Our results suggest the existence of functionally distinct sites related to the D1/D2 receptor classification.