NKP608

NKP608 is a non-peptidic derivative of 4-aminopiperidine which acts as a selective, specific and potent antagonist at the neurokinin-1 (NK-1) receptor both in vitro and in vivo. In vitro, the binding of NKP608 to bovine retina was characterized by an IC50 of 2.6+/-0.4 nM, whereas the compound's affinity to other receptor binding sites, including NK-2 and NK-3, was much lower. Species differences in IC(50) values with NKP608 were less pronounced than with previously described NK-1 receptor antagonists, being 13+/-2 and 27+/-2 nM in gerbil midbrain and rat striatum, respectively. In vivo, using the hind foot thumping model in gerbils, NKP608 exhibited a potent NK-1 antagonistic activity following oral administration (ID(50)=0.23 mg/kg; 2 h pretreatment), supporting a central activity of NKP608. NKP608 may prove a useful anxiolytic compound.

Antagonism by NKP608 of substance P-induced plasma protein exudation in a novel preparation of perfused trachea in rats and guinea-pigs in vivo.[Pubmed:12146722]

Inflamm Res. 2002 Jul;51(7):317-23.

OBJECTIVE: To examine whether NKP608, a novel 1-benzoyl-2-benzyl-4-aminopiperidine NK1 receptor antagonist, inhibits substance P (SP)-induced airway plasma protein exudation in vivo. MATERIAL: Anaesthetised English shorthair guinea-pigs and Wistar rats. TREATMENT: Tachykinin peptides were applied topically onto the trachea and antagonists administered intravenously. METHODS: Tracheal segments isolated in situ were perfused with saline and plasma-derived protein assayed in the perfusate. RESULTS: SP (1 microM) caused plasma protein exudation, which was abolished by an NK1 antagonist (RP 67580,1.75 micromol/kg) but unaffected by an NK2 antagonist (SR 48968, 1.75 micromol/ kg) indicating the response is NK1-receptor-mediated. This was confirmed with a response to an NK1 agonist ([Sar9, Met(O2)11]-SP, 1 microM) but none to an NK2 agonist ([betaAla8]-neurokinin A(4-10), 1 microM). NKP608 inhibited SP responses with estimated ID50 values (micromol/kg) of 0.0044 (guinea-pigs) and 0.19 (rats). CONCLUSIONS: NKP608 is an antagonist in vivo of NK1 receptor-induced tracheal plasma protein exudation and is more potent in guinea-pigs than rats.

The NK1 receptor antagonist NKP608 lacks anxiolytic-like activity in Swiss-Webster mice exposed to the elevated plus-maze.[Pubmed:15302124]

Behav Brain Res. 2004 Sep 23;154(1):183-92.

The selective non-peptide NK(1) receptor antagonist NKP608 has been shown to exert potent anxiolytic-like effects in the rat and gerbil social interaction tests. In vitro binding of NKP608 in cortical, striatal and rest-of-brain tissue samples from mice, rats and gerbils indicated comparable pIC(50) values for rats and mice (in all three tissues) and only slightly higher values for gerbils. It would therefore be expected that doses previously found to produce anxiolytic-like effects in rats and gerbils would also be active in mice. The present study evaluated NKP608 in one of the most widely-used animal models of anxiety, the mouse elevated plus-maze. Two consecutive experiments were conducted in which the effects of NKP608 (0.0003-10.0 mg/kg, p.o.) were compared to those produced by the prototypical benzodiazepine anxiolytic, chlordiazepoxide (CDP, 15 mg/kg, p.o.). Ethological scoring methods were used to provide comprehensive behavioural profiles for each compound. In both experiments, acute CDP treatment resulted in significant anxioselective effects, i.e., reductions in measures of open arm avoidance without any alteration in general activity levels (closed arm entries and rearing). Although the results of Experiment 1 (0.001-10.0 mg/kg NKP608) suggested a weak anxiolytic-like action of NKP608 at 0.001 mg/kg (significant increase in percent open arm entries), Experiment 2 failed both to replicate this effect or to find any behavioural activity at lower (0.0003 mg/kg) or higher (0.03 mg/kg) doses. Present findings suggest that the anxiolytic efficacy of this NK(1) receptor antagonist may be test-specific and thus limited to particular subtypes of anxiety. These new data are also discussed in relation to the general difficulty of relating the behavioural profiles of NK(1) receptor antagonists to their potency at NK(1) receptors.

Effect of a novel NK1 receptor selective antagonist (NKP608) on citric acid induced cough and airway obstruction.[Pubmed:14643166]

Pulm Pharmacol Ther. 2004;17(1):11-8.

The effects of an orally administered novel and selective NK1 antagonist, NKP608, on cough and airway obstruction, induced by citric acid in guinea pigs, were investigated. Guinea pigs were pre-treated with 0.03, 0.3 and 1 mg kg(-1) of NKP608, the NK2 antagonist, SR48968 or both 2 h prior to challenge with citric acid (0.6 M) for a 10 min period. Guinea pigs pre-treated with 0.03, 0.3 and 1mgkg(-1) of NKP608 exhibited a significant reduction of 77, 74 and 79%, respectively, in the numbers of cough compared to vehicle pre-treated animals (P<0.05). SR48968, 10 mg kg(-1), alone did not significantly affect the citric acid-induced cough but when co-administered with 1 mg kg(-1) of NKP608, there was a significant 90% reduction in cough. NKP608 did not significantly reduce the citric acid-induced increase in Penh at any of the doses used. SR48968 significantly reduced the citric acid induced airway obstruction by about 50%. However, when SR48968 was co-administered with NKP608, there was a greater (73%) decrease in the airway obstruction compared with SR48968 alone. These data show that NKP608, a selective NK1 receptor antagonist, is a potent inhibitor of citric acid induced cough in guinea pigs and may therefore have value in the therapy of clinical cough.

Evaluation of the anxiolytic-like effect of NKP608, a NK1-receptor antagonist, in two rat strains that differ in anxiety-related behaviors.[Pubmed:12915956]

Psychopharmacology (Berl). 2003 Nov;170(3):287-293.

RATIONALE: NKP608, a selective NK1 receptor antagonist, has been shown to produce anxiolytic-like effects in rodents tested in different anxiety models. However, most of these findings are based on social behaviors and, to our knowledge, there is no report concerning the effects of NKP608 in the elevated plus-maze (EPM) and the open field (OF), two classical models of anxiety/emotionality. Moreover, this compound has never been tested in rodent strains that display contrasting levels of anxiety-related behaviors. OBJECTIVES: To investigate the anxiolytic-like effects of NKP608 in Lewis and SHR inbred rats, proposed as a genetic model of anxiety for showing high and low indices of anxiety, respectively. METHODS: Lewis and SHR rats of both sexes were tested in the EPM and OF tests following acute administration of NKP608 (0.003, 0.03 or 0.3 mg/kg) or chlordiazepoxide (CDZ, 5 mg/kg). Measures of approach/avoidance towards the open arms of the EPM and the central area of the OF were used as indices of anxiety. RESULTS: All doses of NKP608 produced anxiolytic-like effects, similar to those of CDZ, in SHR males tested in the OF but not in the EPM. Conversely, this compound had a partial anxiolytic effect in LEW males (and, to a lower degree, in SHR females) in the EPM, but not in the OF. LEW females were unaffected following all pharmacological treatments. CONCLUSIONS: These findings indicate that the anxiety-related effects of NKP608 are strain-, sex- and test-dependent. Moreover, the present data confirm and extend the therapeutic potential of NK1 receptor antagonists for the treatment of anxiety.

NKP608 is a non-peptidic derivative of 4-aminopiperidine which acts as a selective, specific and potent antagonist at the neurokinin-1 (NK-1) receptor both in vitro(IC50=2.6 nM) and in vivo.

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