Disease relevance of GR 127935

• GR 127935 showed a trend toward reducing myoclonus [1].

Psychiatry related information on GR 127935

• In wild-type mice, the 5-HT1B agonists CP 94253 (1-10 mg/kg, i.p.) and RU 24969 (0.25-2.0 mg/kg, i.p.) induced a dose-dependent reduction of paradoxical sleep during the 2-6 hr after injection, whereas the 5-HT1B/1D antagonist GR 127935 (0.1-1.0 mg/kg, i.p.) enhanced paradoxical sleep [2].
• To confirm these findings, we tested the effects of MDMA on the locomotor and exploratory behavior of wild-type mice pretreated with GR 127935, a 5-HT1B/1D receptor antagonist [3].
• Reduced locomotor activity following TFMPP was blocked by SB 242084 but not WAY 100635 (0.1 mg/kg s.c.) or GR 127935 (3.0 mg/kg s.c.). Behaviourally relevant levels of 5-HT2C receptor stimulation may not exert reinforcing effects, although other studies indicate that such manipulations alter reinforcing effects of drugs of abuse [4].

High impact information on GR 127935

• Notably, SB-224289 at 1.0mg/kg potentiated a subeffective dose of the 5-HT1B/1D receptor agonist/antagonist mixed GR 127935, which facilitated learning consolidation and this effect was abolished by ketanserin at a higher dose [5].
• Moreover, SB-224289 antagonized the learning deficit produced by TFMPP (a 5-HT1A/1B/1D/2A/2C receptor agonist), GR 46611 (a 5-HT1A/1B/1D receptor agonist), mCPP (a 5-HT2A/2C/3/7 receptor agonist/antagonist) or GR 127935 (at low dose) [5].
• In addition, either the absence of the 5-HT1B receptor or its blockade with the mixed 5-HT1B/1D receptor antagonist, GR 127935, potentiated the effect of a single administration of paroxetine on extracellular 5-HT levels more in the ventral hippocampus than in the frontal cortex [6].
• In contrast, the mixed 5-HT1B/1D receptor antagonist GR-127935 exhibited equal affinity for both isoforms [7].
• SB-224289, which decreased [35S]GTPgammaS binding when given alone, but not GR-127935, was more potent in antagonizing the stimulatory effect of 5-CT on [35S]GTPgammaS binding to membranes expressing the VR compared to membranes expressing the WTR [7].

Biological context of GR 127935

• [(3)H]8-OH-DPAT (in the presence of pindolol and 1 microM RX-821002 for alpha(2) receptor blockade) and [(3)H]5-CT (in the presence of pindolol and GR-127935) bind to a similar receptor binding population corresponding to 5-HT(7) binding sites [8].
• Pretreatment with GR 127935 (0.63 mg/kg, n = 5) abolished the fall in venous oxygen saturation and the increase in carotid vascular resistance and reduced the increases in pVCO(2) induced by donitriptan [9].

Anatomical context of GR 127935

• In basal ganglia and midbrain, this effect was blocked by GR 127935 (5-HT(1B/1D) antagonist) [10].
• The 5-HT reuptake inhibitor fluoxetine contracted smooth muscle strips, a contraction that was partially inhibited by GR-127935 and abolished by tetrodotoxin [11].
• Low to moderate densities of [(3)H]5-CT (2 nM) binding sites insensitive to pindolol (10 microM, for 5-HT(1A/1B) receptor blockade) and GR-127935 (1 microM; for 5-HT(1D) receptor blockade) were observed in wild-type mice (mainly in thalamus and hypothalamus) but not in 5-HT(7) receptor knockout mice [8].
• In the dentate gyrus (median raphe innervated area), GR 127935 and SB-224289 significantly increased extracellular 5-HT, reaching maxima of 146+/-11% and 151+/-19% of basal, respectively [12].
• We now present data with the novel 5-HT1D receptor antagonist, GR 127935, which demonstrates that in guinea pig cerebral cortex the terminal autoreceptor is a 5-HT1D receptor [13].

Associations of GR 127935 with other chemical compounds

• However, pretreatment with an intermediate dose of GR 127935 (3 mg/kg), which was previously without effect on ICSS behavior, reversed the threshold-elevating effects of RU 24969 (1 mg/kg), suggesting the involvement of the 5-HT1B receptor in this effect of RU 24969 administration [14].
• The response pattern to fluoxetine alone in 5-HT receptor mutant mice corresponded with the effects of fluoxetine given with either the 5-HT(1A) receptor antagonist WAY 100635 (0.1 mg/kg i.p.) or the 5-HT(1B/1D) receptor antagonist GR 127935 (0.056 mg/kg) in wild-type mice [15].
• Blockade of porcine carotid vascular response to sumatriptan by GR 127935, a selective 5-HT1D receptor antagonist [16].
• The reduction in aggression was antagonized by GR 127935, indicated by a rightward shift in the dose-effect curves of zolmitriptan, showing the specificity for the 5-HT1B receptors [17].
• In addition, the discriminative stimulus produced by CP-135,807 was not blocked by WAY 100,635, a selective 5-HT1A antagonist, but was completely and dose-dependently antagonized by the selective 5-HT1D antagonist, GR 127935 [18].

Gene context of GR 127935

• Metergoline and the selective 5-HT 1B/D receptor ligands GR 127935 as well as GR 125743 showed significant intrinsic activity (43% to 69%) at the 5-HT 1D receptor subtype, whereas the nonselective ligand 1-naphthylpiperazine yielded less (15% to 19%) intrinsic activity at both receptor subtypes [19].
• Furthermore, the hyperlocomotion produced by m-CPP in the presence of LY53857 (1.0 mg/kg) was blocked by both the 5-HT(1B/1D) receptor antagonist GR 127935 (3.0 mg/kg) and the 5-HT1A receptor antagonist WAY 100,635 (1.0 mg/kg) [20].
• The inhibitory effect of 5-CT was blocked by the 5-HT1/2 antagonist methiothepin (1 microM), the 5-HT1A antagonist S-UH-301 (1 microM), and the 5-HT1B/1D antagonist GR 127935 (1 microM) [21].
• GR 127935 (1 mg/kg, s.c.), SB 200646A (without effect per se at 10 mg/kg, s.c.) and MDL 100,151 (0.3 mg/kg, s.c.) did not inhibit the cataleptic response to the dopamine D2 receptor antagonist, loxapine (0.3 mg/kg, s.c [22].
• 5-HT7 binding sites were labelled in rat and guinea pig brains by incubating with 3H-5-CT in the presence of 100 microM WAY 100135 and 250 microM GR 127935; the distribution obtained in both species agreed, in general, with that of the corresponding mRNA coding for them [23].

Analytical, diagnostic and therapeutic context of GR 127935

• On the other hand, PA constriction to 5-HT was attenuated by either the addition of GR-127935 (0.1 microM, a selective inhibitor of 5-HT(1B/1D) receptor) or copper/zinc-containing superoxide dismutase (Cu/Zn SOD, 150 U/ml) and in PA isolated from transgenic mice overexpressing human EC-SOD [24].
• In vivo, using the technique of microdialysis, GR 127935 and the non-selective antagonist methiothepin, when administered down the dialysis probe, potentiate extracellular levels of 5-HT [13].

References