NKP608: a selective NK-1 receptor antagonist with anxiolytic-like effects in the social interaction and social exploration test in rats

NKP608 is a non-peptidic derivative of 4-aminopiperidine which acts as a se lective, 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 retin a was characterized by an IC50 of 2.6+/-0.4 nM, whereas the compound's affi nity to other receptor binding sites. including NK-2 and NK-3. was much low er. Species differences in IC50 values with NKP608 were less pronounced tha n with previously described NK-1 receptor antagonists, being 13+/-2 and 27/-2 nM in gerbil midbrain and rat striatum, respectively. In vivo, using th e hind foot thumping model in gerbils, NKP608 exhibited a potent NK-1 antag onistic activity following oral administration (ID50 = 0.23 mg/kg, 2 h pret reatment), supporting a central activity of NKP608. The compound had a long duration of action with an ID50 value of 0.15 mg/kg p.o. and 0.38 mg/kg p. o. following a pretreatment of 5 and 24 h, respectively. Following a subchr onic administration for 7 consecutive days (once daily) there was no eviden ce for the development of tolerance or accumulation. In the social interact ion test performed in a highly illuminated, unfamiliar test arena, NKP608 s pecifically increased the time the two rats spent in social contact, and th ere was no concomitant increase in parameters reflecting general activity, i.e. ambulation (number of square entries) or the number of rearings. Activ e social time was maximally increased at a dose range of 0.01-1 mg/kg p.o. NKP608, the effect bring weaker or absent at both lower (0.001 mg/kg p.o.) and higher (10 mg/kg p.o.) doses. A comparable bell-shaped dose-response re lation was seen in the social exploration test in rats. In this modified re sident/intruder paradigm. maximal increase in social contact of the intrude r rat directed towards the resident rat was seen at a similar dose range (0 .03-3 mg/kg p.o.) The effects observed following an acute oral administrati on of NKP608 were comparable to those seen following a treatment with the w ell-known benzodiazepine, chlordiazepoxide. in both these tests. These find ings indicate that NKP608 exhibits an anxiolytic-like effect and that this effect, as concluded from the observed antagonism of the hind foot thumping induced by i.c.v. administration of the NK-1 receptor agonist SPOMe, is ce ntrally mediated. This makes this compound a potentially promising candidat e for treating anxiety-related disorders in humans. (C) 2000 Elsevier Scien ce B.V. All rights reserved.