U 99194 maleate

Dopamine D1 receptors synergize with D2, but not D3 or D4, receptors in the striatum without the involvement of action potentials.[Pubmed:10964971]

J Neurosci. 2000 Sep 1;20(17):6666-71.

The widespread biological actions of the neurotransmitter dopamine (DA) are mediated by two classes of receptor, the D(1) class (D(1) and D(5)) and the D(2) class (D(2), D(3), and D(4)), which interact synergistically in many paradigms, such as DA agonist-stimulated motor behavior and striatal c-fos expression. Understanding the mechanism(s) of this interaction has been impeded by a controversy regarding the cellular localization of D(1) and D(2) class receptors. To address this issue from a functional point of view, we elicited striatal Fos by combined administration of a D(1) class and a D(2) class agonist either in the presence or absence of the fast sodium channel blocker tetrodotoxin (TTX). Striatal Fos elicited by direct D(1)/D(2) stimulation was not reduced by TTX. By contrast, TTX greatly attenuated the Fos response evoked by cocaine or GBR 12909. In separate experiments using antagonists that distinguish among members of the D(2) class of receptors, amphetamine-stimulated Fos and motor behavior were attenuated dose-dependently by the selective D(2) antagonist L-741,626, but not by the selective D(3) antagonist U99194A or the D(4)-selective antagonist L-745,870. Because Fos expression in the paradigms that were used occurs in enkephalin-negative striatonigral neurons, which show limited coexpression of D(1) and D(2) receptors, the present findings taken together suggest the intriguing possibility that D(1)/D(2) synergism may be mediated by D(1) and D(2) receptors residing on separate striatal neurons and interacting in a manner that is not dependent on action potentials.

A comparative in vitro and in vivo pharmacological characterization of the novel dopamine D3 receptor antagonists (+)-S 14297, nafadotride, GR 103,691 and U 99194.[Pubmed:9765337]

J Pharmacol Exp Ther. 1998 Oct;287(1):187-97.

The benzofurane (+)-S 14297, the benzamide nafadotride, the aminoindane U 99194 and the arylpiperazine GR 103,691 have been proposed as "selective" antagonists at dopamine D3 vs. D2 receptors. Herein, we compared their in vitro affinities and in vivo actions to those of the aminotetralin D3 antagonists (+)-AJ 76 and (+)-UH 232. Affinities at recombinant, human (h)D3 and/or hD2 sites were determined by employing the mixed D2/D3 antagonist [125I]-iodosulpride and the preferential D3 ligands [3H]-(+)-PD 128, 907 and [3H]-(+)-S 14297. [3H]-(+)-PD 128,907, [3H]-(+)-S 14297 and [125I]-iodosulpride yielded an essentially identical pattern of displacement at D3 sites, which suggests that they recognize the same population of receptors. The rank order of potency (Ki values in nM vs. [3H]-(+)-PD 128,907) was GR 103,691 (0.4) approximately nafadotride (0.5) > haloperidol (2) approximately (+)-UH 232 (3) approximately (+)-S 14297 (5) > (+)-AJ 76 (26) > U 99194 (160). The rank order of preference (Ki ratio, D2:D3) for D3 receptors (labeled by [3H]-PD 128,907) vs. D2 sites (labeled by [125I]-iodosulpride) was (+)-S 14297 (61) approximately GR 103,691 (60) > U 99194 (14) > nafadotride (9) approximately (+)-UH 232 (8) approximately (+)-AJ 76 (6) > haloperidol (0.2). (+)-S 14297 and GR 103,691 also showed greater than 100-fold selectivity at dopamine hD3 vs. hD4 and hD1 sites. However, GR 103,691 showed marked affinity for serotonin1A receptors (5.8 nM) and alpha-1 adrenoceptors (12.6 nM). In vivo, all antagonists except GR 103,691 prevented the induction of hypothermia by (+)-PD 128,907 (0.63 mg/kg s.c.) and a further preferential D3 agonist, (+)-7-OH-DPAT (0.16 mg/kg s.c.). On the other hand, haloperidol, (+)-AJ 76, (+)-UH 232 and nafadotride all induced catalepsy in rats, whereas (+)-S 14297, U 99194 and GR 103,691 were inactive. Haloperidol, (+)-AJ 76, (+)-UH 232, nafadotride and (weakly) U 99194 also enhanced prolactin secretion and striatal dopamine synthesis, whereas (+)-S 14297 and GR 103,691 were inactive. However, despite its high affinity at 5-HT1A receptors and alpha-1 adrenoceptors, both of which are present on raphe-localized serotonergic neurons, GR 103,691 (0.5 mg/kg i.v.) failed to influence their basal firing rate or the inhibition of their electrical activity by the 5-HT1A agonist (+/-)-8-OH-DPAT (0.005 mg/kg i.v.), a result that casts doubt on its activity in vivo. In conclusion, both (+)-S 14297 and GR 103,691 are markedly selective ligands that permit the characterization of actions at hD3 vs. hD2 receptors in vitro, but (+)-S 14297 appears to be of greater utility for the evaluation of their functional significance in vivo. Nevertheless, to develop a better understanding of the respective roles of dopamine D3 and D2 receptors, we need additional, chemically diverse antagonists of improved potency and selectivity.

Heterogeneity of behavioural profile between three new putative selective D3 dopamine receptor antagonists using an ethologically based approach.[Pubmed:9566814]

Psychopharmacology (Berl). 1998 Apr;136(3):284-90.

The effects on behaviour of the putative selective D3 dopamine receptor antagonists GR 103691, nafadotride and U 99194A were compared with those of the generic D2-like antagonist haloperidol, using an ethologically based approach. Neither GR 103691 (0.008-1.0 mg/kg) nor nafadotride (0.025-1.6 mg/kg) influenced any element of behaviour. Conversely, U99194A (1.67-45 mg/kg) effected a dose-dependent stimulation of episodes of non-stereotyped sniffing, locomotion, chewing and eating, with some stimulation of rearing, and reduced baseline levels of grooming; thereafter, as sniffing and locomotion declined, stimulation of episodes of grooming emerged. Haloperidol (0.0008-0.1 mg/kg) failed to promote any element of behaviour and reduced baseline levels of grooming; responsivity to U99194A was antagonised by pretreatment with haloperidol. The lack of effect of GR 103691 (> 100-fold D3/D2 selectivity) and nafadotride (10-fold D3/D2 preference), in contrast to the characteristic "ethogram" for U99194A (25-fold D3/D2 selectivity), indicated a fundamental difference in their mechanisms of action. This topography of responsivity to U99194A overlapped somewhat with the profiles of both D2-like and D1-like agonists, and its sensitivity to antagonism by haloperidol also indicated a dopaminergic basis thereto. However, differences among GR 103691, nafadotride and U99194A bore no relation to their relative selectivities for the D3 receptor, and the basis thereof remains unclear. Theorising as to the behavioural role of the D3 receptor may need to be tempered pending the identification of a range of chemically distinct D3 antagonists of higher selectivity.