L 760735

The substance P (NK1) receptor antagonist L-760735 inhibits fear conditioning in gerbils.[Pubmed:12646288]

Neuropharmacology. 2003 Mar;44(4):516-23.

The ability of the substance P (NK(1) receptor) antagonist (SPA) L-760735 to inhibit conditioned fear was assessed in gerbils using a four plate apparatus. Animals that had been treated with diazepam (3 mg/kg) or L-760735 (3 mg/kg) 30 min before a 3 min conditioning session in the apparatus exhibited a release of plate crossings during the retest session approximately 3 h later. Plate crossings were also increased when animals received diazepam or L-760735 30 min before the retest session. In contrast, fluoxetine and venlafaxine (30 mg/kg) did not exhibit anxiolytic-like effects. During the retest session, gerbils drummed their hind feet on the floor; this behaviour was not observed spontaneously in gerbils that were naive to the apparatus. Foot drumming was abolished by pretreatment with L-760735 or diazepam (3 mg/kg) but was markedly increased following administration of fluoxetine or venlafaxine (30 mg/kg). Foot drumming elicited by aversive conditioning alone or in combination with fluoxetine was abolished by administration of L-760735 and by amygdala lesions involving the basolateral and lateral nuclei, indicating that this behaviour is an alarm signal or fear response mediated via release of substance P in brain circuits involving the amygdala. The observations provide further evidence for an anxiolytic-like profile of SPAs in preclinical assays and demonstrate a clear difference between the actions of SPAs and established antidepressant drugs.

Chronic psychosocial stress in tree shrews: effect of the substance P (NK1 receptor) antagonist L-760735 and clomipramine on endocrine and behavioral parameters.[Pubmed:15875166]

Psychopharmacology (Berl). 2005 Sep;181(2):207-16.

RATIONALE: Substance P and its preferred receptor, the neurokinin 1 receptor (NK(1)R), have been proposed as possible targets for new antidepressant therapies, although results of a recently completed phase III trial failed to demonstrate that the NK(1)R antagonist MK-869 is more effective than placebo in the treatment of depression. METHODS: In the present study, we compared the effects of the NK(1)R antagonist L-760735 with the tricyclic antidepressant clomipramine on endocrine and behavioral parameters in chronically stressed tree shrews. Animals were subjected to a 7-day period of psychosocial stress before receiving daily oral administration of L-760735 (10 mg/kg/day) or clomipramine (50 mg/kg/day). The psychosocial stress continued throughout the treatment period of 21 days. Daily morning urine was collected to measure cortisol and norepinephrine levels. All animals were videotaped daily and three types of behavior were analyzed. RESULTS: Chronic psychosocial stress resulted in a significant increase of urinary cortisol and norepinephrine concentrations. Moreover, stressed animals displayed decreased marking behavior and locomotor activity, while grooming remained unaffected. Neither treatment with clomipramine nor L-760735 was able to normalize the stress-induced elevation of cortisol or norepinephrine. On the behavioral parameters, L-760735 had a time-dependent restorative influence on marking behavior close to normal levels, without affecting locomotor activity. Grooming behavior was significantly increased by the 3 weeks of drug treatment. CONCLUSIONS: These results suggest that L-760735 was able to counteract certain stress-induced behavioral alterations in an animal model of depression.

Anxiolytic actions of the substance P (NK1) receptor antagonist L-760735 and the 5-HT1A agonist 8-OH-DPAT in the social interaction test in gerbils.[Pubmed:11595206]

Brain Res. 2001 Oct 12;915(2):170-5.

The gerbil social interaction test has previously detected anxiolytic effects of nicotine and diazepam. In the present study, the high affinity substance P (NK(1)) receptor antagonist L-760735 (3 mg/kg) significantly increased the time spent in social interaction, whereas its low affinity analogue L-781773 (3 mg/kg) was without effect. Diazepam (0.1 mg/kg) and the 5-HT(1A) receptor agonist 8-OH-DPAT (0.003 and 0.01 mg/kg) also increased social interaction, whereas an acute dose of the selective serotonin re-uptake inhibitor fluoxetine (10 mg/kg) decreased the time spent in social interaction. Diazepam (0.1 mg/kg) significantly increased locomotor activity, but this effect was independent of the increase in social interaction. The other drugs tested were without effect on locomotor activity. The present findings suggest that the gerbil social interaction may well provide a useful assay for detecting both anxiolytic and anxiogenic compounds, and suggests that the high affinity NK(1) receptor antagonist L-760735 may prove to be useful as an anxiolytic therapy.

Intra-amygdala injection of the substance P [NK(1) receptor] antagonist L-760735 inhibits neonatal vocalisations in guinea-pigs.[Pubmed:11445193]

Neuropharmacology. 2001 Jul;41(1):130-7.

The involvement of the basolateral amygdala in mediating the inhibition of neonatal vocalisation by substance P (NK(1) receptor) antagonists was examined. These studies determined whether the time course for separation-induced vocalisations in guinea-pig pups coincided with NK(1) receptor internalisation (a marker of substance P release) in the amygdala, and whether vocalisations could be blocked by focal injection of the NK(1) receptor antagonist L-760735 into this brain region. The peak period for neonatal vocalisations occurred 5-10 min following maternal separation. This coincided with the peak increase in the number of cells in the basolateral amygdala exhibiting NK(1) receptor endocytosis, consistent with the proposal that substance P is released in the amygdala as a result of isolation stress. Focal injection of L-760735 (15 nmol per side) but not L-770765 (an analogue of L-760735 which has low NK(1) receptor affinity) into the basolateral amygdala attenuated separation-induced vocalisations. In contrast, injection of L-760735 (15 nmol per side) into the dorsal ventricular nucleus of the thalamus, a region with relatively low density of NK(1) receptors, had no effect on neonatal vocalisations. These findings are consistent with other evidence that the amygdala is one possible site of action for the inhibition of neonatal vocalisations by substance P antagonists.

Correlation of neurokinin (NK) 1 receptor occupancy in gerbil striatum with behavioral effects of NK1 antagonists.[Pubmed:11961054]

J Pharmacol Exp Ther. 2002 May;301(2):536-42.

Interest in central neurokinin (NK) 1 receptors has increased based on reports of the therapeutic potential for NK1 antagonists in anxiety and depression. In these studies, an ex vivo binding procedure was used to correlate NK1 receptor occupancy in striatum by NK1 antagonists with their potency to inhibit NK1 agonist-induced foot tapping in gerbils (GFT). The following compounds were administered orally: CP-99,994 [(+)-cis-n-[(2-methoxyphenyl)methyl]-2-phenyl-3-piperidinamine), L-742,694 [5-[[2(S)-[[3,5-bis(trifluoromethyl)phenyl]methoxy]-3(S)-phenyl-4-morpholinyl]met hyl]-2,4-dihydro-3H-1,2,4-triazol-3-one]), MK-869 [5-[[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)-4-m orpholinyl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one], CP-122,721 [cis-n-[[2-methoxy-5-(trifluoromethoxy)phenyl]methyl]-2-phenyl-3-piperidinamine], L-760,735-F [4-[[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)-4-m orpholinyl]methyl]-N,N-dimethyl-1H-1,2,3-triazole-5- methanamine], GR205171 [N-[[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]phenyl]methy]-2(S)-phenyl- 3(S)-piperidinamine], L-733,060 [(2S,3S)3-([3,5-bis(trifluoro methyl)phenyl]methoxy)-2-phenylpiperidine], and L-733,061 [(2R,3R)-3-([3,5-bis(trifluoromethyl)phenyl]methoxy)-2-phenylpiperidine]. Two hours later, gerbils received the NK1 agonist GR73632 [H(2)N-(CH(2))(4)-CO-Phe-Pro-NMe-Leu-Met-NH(2)] i.c.v. and foot tapping was measured for 5 min. The same procedure was used for ex vivo binding studies except that saline, rather than agonist, was administered i.c.v. before dissection of the striatum. The tissue homogenate was then used in an equilibrium radioligand binding assay. When IC(50) values for inhibition of ex vivo (125)I-substance P binding by NK1 antagonists were compared with the corresponding EC(50) values for inhibition of GFT, a significant positive correlation was observed (r(2) = 0.97, p < 0.001). This result indicates that increased NK1 receptor occupancy in striatum by NK1 antagonists parallels the inhibition of agonist-mediated GFT. For all compounds, the dose that produced the maximum inhibition of GFT resulted in less than 100% ex vivo receptor occupancy in striatum. When gerbils did not receive the i.c.v. saline injection before ex vivo binding, thereby leaving the blood-brain barrier (BBB) intact, the IC(50) values for antagonists were unchanged, suggesting that potential damage to the BBB caused by the i.c.v. injection did not affect determinations of antagonist potency in the GFT model.

An orally active, water-soluble neurokinin-1 receptor antagonist suitable for both intravenous and oral clinical administration.[Pubmed:11708932]

J Med Chem. 2001 Nov 22;44(24):4296-9.

1-(5-[[(2R,3S)-2-([(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorop henyl)morpholin-4-yl]methyl]-2H-1,2,3-triazol-4-yl)-N,N-dimethylmethanamine hydrochloride 3 is a high affinity, orally active, h-NK(1) receptor antagonist with a long central duration of action and a solubility in water of >100 mg/mL. The construction of the 5-dimethylaminomethyl 1,2,3-triazol-4-yl unit, which incorporates the solubilizing group of 3, was accomplished by thermal rearrangement of a propargylic azide in the presence of dimethylamine. Compound 3 is highly effective in pre-clinical tests that are relevant to clinical efficacy in emesis and depression.