Affinity For Dopamine D2 Receptors Research Articles

Development of a receptor-interaction model for serotonin 5-HT2 receptor antagonists. Predicting selectivity with respect to dopamine D2 receptors.

A receptor-interaction model for serotonin 5-HT2 receptor antagonists has been developed by conformational analysis with molecular mechanics (MM2(91)) and superimposition studies of serotonin 5-HT2 receptor antagonists. Substituted 3-(4-piperidinyl)-,1-(4- piperidinyl)-,3-(1,2,3,6-tetrahydropyridin-4-yl)-, and 1-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles, substituted 3-(4-fluorophenyl)-1-(4-piperazinyl)indans, cyprohepatadine derivatives, ritanserin, and danitracene have been used as bases for the model. Other serotonin 5-HT2 receptor antagonists, such as ketanserin and MDL 11,939, are well accommodated into the model. Comparison of the model with a recently described receptor-interaction model for dopamine D2 receptor antagonists suggests a common pharmacophore for dopamine D2 and serotonin 5-HT2 receptor antagonists. Important steric differences between 5-HT2 receptor antagonists with additional high affinity for dopamine D2 receptors and serotonin 5-HT2 receptor antagonists with high selectivity versus D2 receptors are described. The geometry of the receptor-interaction model described is significantly different from that of a recently reported receptor-interaction model for 5-HT2 receptor agonists and antagonists developed by use of (+)-LSD as a template, suggesting the existence of two binding modes at the 5-HT2 receptor.

Myocardial accumulation of a dopamine D2 receptor-binding radioligand, 2'-iodospiperone.

125I-2'-iodospiperone (2'-ISP), which has a high and selective affinity for dopamine D2 receptors, produced a high myocardial accumulation of radioactivity in the early phase after intravenous injection into mice. A human scintigraphic study also showed that the myocardium was clearly visualized soon after intravenous injection of the tracer. Analysis of the myocardial homogenate obtained from mice showed that 125I-2'-ISP was metabolically stable and was taken up the myocardium in its intact form. Administration of spiperone significantly reduced the myocardial uptake of 125I-2'-ISP in mice. Treatment with haloperidol and (+) butaclamol, which have a high affinity for dopamine D2 receptors, also tended to reduce the myocardial uptake of radioactivity, while (-)-butaclamol, which has no affinity for dopamine D2 receptors, caused no change in uptake. These findings suggest that the myocardial accumulation of 2'-ISP occurred in association with dopamine D2 (DA2) receptors.

Novel piperidine sigma receptor ligands as potential antipsychotic drugs.

sigma receptor ligands represent a new class of potential antipsychotic drugs. This paper presents the structure-activity relationships leading to novel disubstituted piperidine sigma ligands, which have little or no affinity for dopamine D2 receptors. Selectivity for sigma sites over dopamine D2 or serotonin 5-HT2 receptors appears to be governed by the chemical nature of the piperidine nitrogen substituent, its distance from the basic nitrogen, and its orientation relative to the other piperidine substituent. Several of these compounds have good oral potency in some animal models used to evaluate potential antipsychotic drugs. The N-cyclopropylmethyl ketones and ethers (e.g. 6i (DuP 734), 6q, 18a, and 18n) have the best in vivo potency. Compounds 6i (DuP 734) and 6q did not cause catalepsy in the rat, even at very high doses. On the basis of the pharmacology profiles of these sigma ligands, we propose these compounds may be effective antipsychotic drugs, which do not induce extrapyramidal side effects or tardive dyskinesia.

Novel phenoxyalkylamine derivatives. VII. Synthesis and pharmacological activities of 2-alkoxy-5-[(phenoxyalkylamino)alkyl]benzenesulfonamide derivatives.

To find a novel alpha-blocker with high alpha-blocking selectivity against dopamine D2-receptor affinity, we performed structural modification of the alkylene chains and the substituents on two benzene rings of 2-alkoxy-5-[(phenoxyalkylamino)alkyl]benzenesulfonamide derivatives. The modification of the alkylene chain between the amino moiety in the center of the molecule and the benzene ring (ring A) was found to be the most significant. 5-[2-[[2-(5-Fluoro-2-methoxyphenoxy)ethyl]amino]propyl]-2- methoxybenzenesulfonamide (II-4), which possesses 1-methylethyl as the alkylene chain, exhibited high alpha-blocking selectivity as well as potent alpha-blocking activity.

Molecular Basis of Buspirone's Anxiolytic Action

Buspirone has been available in the United States for over four years for the treatment of anxiety. It was anticipated this drug would offer certain advantages over the established benzodiazepines. In contrast to diazepam, early studies found no evidence for the interaction of buspirone with GABAergic mechanisms. Behavioural, electrophysiological and receptor binding experiments gradually led to the idea that buspirone owes much of its anxiolytic activity to its ability to attenuate central 5-hydroxytryptamine neurotransmission. Specifically, it appears to act as an agonist at presynaptic 5-HT1A receptors, particularly in the raphe nuclei. Although buspirone also shows an affinity for dopamine D2 receptors, where it seems to behave as an antagonist, there is much doubt that this effect is related to its anxiolytic action. Even though buspirone and the benzodiazepines do not obviously share a common mode of action, the possibility is discussed that there is an underlying common mechanism of responsible for their antianxiety effects.

Neurochemical profile of EMD 45609 (carmoxirole), a dopamine DA2-receptor agonist

A new potential antihypertensive drug, EMD 45609 (carmoxirole), has been characterized in various in vivo and in vitro models. EMD 45609 displayed high affinity for dopamine D2-receptors combined with negligible binding to D1-receptors in binding assays in vitro. However, in tests in vivo for central D2-receptor activity, EMD 45609 exhibited only weak activity. Thus, after p.o. administration, striatal L-DOPA accumulation in intact rats was unchanged up to 100 mg/kg p.o., i.e. doses 100 times higher than those reported to induce depressor activity. Central dopamine agonistic activity could only be verified in the more sensitive model of the reserpinized rat. EMD 45609 was more than 30 times less potent, however, than LY 141865 in reserpinized rats after s.c. administration. Similarly, in rats with 6-hydroxydopamine induced unilateral lesions of the substantia nigra, EMD 45609 was only marginally active. The shallow dose response curves and the submaximal effects obtained for central dopaminergic activity, as reflected in the inhibition of striatal L-DOPA accumulation, suggest that EMD 45609 is a partial dopamine D2-receptor agonist and in addition, owing to its ionizable structure, passes less readily into the brain than several reference compounds. A marked affinity was found towards 5-HT1A-receptors in vitro, whereas affinity for alpha 1- and alpha 2-adrenoceptors was low; accordingly, central alpha 2-adrenoceptor activity was not detected as EMD 45609 failed to affect hypothalamic L-DOPA accumulation even at 100 mg/kg s.c. In accordance with its high affinity for D2-receptors in vitro, EMD 45609 inhibited field stimulated noradrenaline release from rabbit ear arteries in nanomolar threshold concentrations at 0.5 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)

Phenytoin potentiation of neuroleptic‐induced dyskinesias

Clinically phenytoin-induced movement disorders may resemble neuroleptic-induced tardive dyskinesia (TD). Neuroleptic-induced TD is thought to be related to an increase in the number and affinity of dopamine D2 receptors. We investigated the interaction of phenytoin with dopaminergic systems by measuring dopamine behavior and receptor changes in animals treated with phenytoin alone or in combination with chlorpromazine. Phenytoin alone or in combination produced significant behavioral supersensitivity without alteration of dopamine D2 receptor density or affinity. This animal study suggests that phenytoin may aggravate neuroleptic-induced tardive dyskinesia through mechanisms other than the dopamine D2 receptors.

Repeated Administration of Antidepressants Enhances Agonist Affinity for Mesolimbic D2-Receptors

Studies have shown an increased responsiveness of the dopaminergic system after repeated administration of a variety of antidepressant drugs. In the present study, the effect of repeated administration (twice daily for 14 days) of imipramine and mianserin on the affinity of dopamine D2-receptors for quinpirole, a D2-agonist, and on the quinpirole-induced locomotor hyperactivity was examined in rats. Repeated doses of imipramine and mianserin increased the affinity of quinpirole for [3H]spiperone binding sites in membranes prepared from the limbic system but not the striatum. The locomotor hyperactivity induced by quinpirole was enhanced by chronic treatment with both antidepressants. The data indicate that the enhanced responsiveness of the dopaminergic system in rats, observed after chronic treatment with antidepressants, may result from an increased affinity of agonists at D2-receptors in the mesolimbic system.

Time-dependent effects of estradiol and progesterone on the number of striatal dopaminergic D2-receptors

Recent evidence has shown that sexual steroids are able to modify the activity of the dopaminergic nigrostriatal pathway. Most of this evidence has been obtained from the individual effects of these hormones, but there is less information about possible interrelationships between both. In order to further explore this question, ovariectomized adult rats were submitted to estradiol (E 2) or vehicle injections during 3 days and, at the third day, were also submitted to a single injection of progesterone (P) or vehicle at 4, 10, 24 and 32 h before decapitation. Additionally, the effect of injections of 2-hydroxyestradiol (2OH-E 2), which has been involved as local mediator in the effects of E 2, was also examined. The two striata of each animal were removed and used for determination of number and affinity of dopamine D2-receptors, using [ 3H]spiroperidol as ligand. Administration of E 2 produced a significant reduction in the number of striatal dopaminergic receptors 10 h after the last steroid injection, which was followed by an increase at 24 h. Administration of P briefly decreased the number of dopaminergic receptors at 4 h after the steroid injection. This effect was not observed in animals pretreated with E 2, in which administration of P produced an apparent increase 24 h after the steroid treatment. On the other hand, the 2-hydroxylated derivative of E 2 does not seem to mediate in the stimulatory action of this estrogen, since it was unable to increase the number of dopaminergic receptors by itself or priming the action of P. The affinity of dopaminergic receptors for [ 3H]spiroperidol was not significantly altered after all the steroid treatments. These results allow us to conclude that both sexual steroids have a dual effect on striatal dopaminergic receptors. Estradiol produced an inhibition followed by an increase in the density of these receptors in the striatum, which was not mediated by 2OH-E 2. Progesterone also caused an inhibition followed by a stimulation in the number of striatal dopaminergic receptors. However, the stimulatory effect needed the previous action of E 2, whereas the inhibition was only produced in animals non-pretreated with estrogens.

Dopaminergic binding and inhibitory effect in the bovine adrenal zona glomerulosa.

Dopaminergic mechanisms may be involved in the regulation of aldosterone secretion in humans and in the rat. Whether these effects are indirect or are exerted directly at the adrenal level has not yet been resolved. We now report the identification of dopaminergic binding sites in the bovine adrenal zone glomerulosa using [3H]spiperone, a butyrophenone with high affinity for D2 dopamine receptors. Specific [3H]spiperone binding (defined as binding displaceable by 10 microns (+)-butaclamol) reached equilibrium within 20 minutes at 22 degrees C, was reversible, and was heat labile (60 degrees C). Binding was of high affinity and saturable with a Kd of 1.8 +/- 0.2 nM and maximal specific binding of 38 +/- 8 fmol/mg (means +/- SEM; n = 18). [3H]Spiperone binding was unaffected by coincubation with angiotensin II, adrenocorticotropic hormone, or KCl. Binding characteristics, including a dissociation constant at the nanomolar range, greater potency of the D2-agonist LY 171555 relative to the D1-agonist SKF 38393 in inhibiting [3H]spiperone binding, and lack of stimulation of cyclic adenosine 3',5'-monophosphate by dopamine (10(-4) M), were consistent with a predominantly D2-receptor. In vitro studies with collagenase-dispersed adrenal zona glomerulosa cells showed that dopamine (10(-4) M) attenuated angiotensin II-stimulated aldosterone secretion. These observations are consistent with a direct inhibitory effect of dopamine on aldosterone secretion in the adrenal zona glomerulosa.