gr-103691 and nafadotride

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.

Topics: Animals; Behavior, Animal; Biphenyl Compounds; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Drug Interactions; Grooming; Haloperidol; Indans; Male; Motor Activity; Naphthalenes; Piperazines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D3; Stereotyped Behavior

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 permi

Topics: 2-Naphthylamine; 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Benzopyrans; Binding, Competitive; Biphenyl Compounds; Body Temperature; Catalepsy; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Furans; Humans; Indans; Naphthalenes; Oxazines; Piperazines; Prolactin; Pyrrolidines; Rats; Receptors, Dopamine D2; Receptors, Dopamine D3