NKi antagonist

A great number of preclinical studies describes anxiogenic effects of substance P (Commons and Valentino 2002), and anxiolytic effects of NKi antagonists (Vassout et al. 2000). Disruption of the NKi receptor by knockout techniques results in mice with reduced anxiety in response to stress (Santarelh et al. 

TAK-637 is a potent and selective neurokinin NKi antagonist being studied (Phase II) for its potential in the treatment of urinary incontinence (Figure 8.81). 

In mice, three further NKi antagonists - SR140,333, WIN51,708 and WIN62.577 - inhibited the late phase of formalin-induced licking, but failed to modify the tail-flick... 

Moreover, duration of central NKi receptor blockade is a critical point, as anesthetic-like nerve block caused by non-specific effects on ion channels in peripheral tissues could mask the selective antinociceptive effects of blocking NKi receptors in the spinal cord. The long-acting NKi antagonist L-733,060 maintained blockade of central NKi receptors at a time when peak plasma drug levels had subsided. Therefore, in paw licking experiments, the inhibitory effect of L-733,060 appeared to be due to central NKi receptor blockade (Rupniak et al., 1996). 

Ryckmans, T, Balan9on, L., Berton, O., Genicot, C., Lamberty, Y., Lallemand, B., Pasau, P, Pirlot, N., Quere, L., Talaga, P. First dual NKi antagonists-serotonin reuptake inhibitors synthesis and SAR of a new class of potential antidepressants. Bioorg. Med. Chem. Lett. 

I Neurokinin (NK, substance P) can be anxiogenic in laboratory animals. NKi antagonists are anxiolytic in some animal models where they are not as potent as BDZs but better than SSRIs. 

For instance, the undecapeptide substance P is a neurotransmitter that mediates diverse biological responses in the nervous and immune systems mainly through the NK) GPCR. The specific response of the hormone depends on the location of the NKi receptor, and pain, neurogenic inflammation, asthma, and emesis are currently discussed as potential therapeutic indications for NKi antagonists. The knowledge of the tissue distribution is thus essential to predict potential main and side activities. 

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