Tachykinins, a family of small peptides that share a common C-terminal sequence, are widely distributed in smooth muscle, peripheral nerves, the spinal cord and the brain. The actions of the five tachykinins are mediated primarily, but not exclusively, through three subtypes of receptors belonging to the G-protein linked neurokinin receptor family -- neurokinin Type 1 (NK1), neurokinin Type 2 (NK2), and neurokinin Type 3 (Nk30. The actions of Substance P, neurokinin A (NKA), and neurokinin B (NKB) (the three most common tachykinins) have been linked most closely with NK1, NK2, and NK3 receptors, respectively. Substance P, the most abundant mammalian tachykinin isolated, displays highest affinity for NK1. Substance P is located in several regions of the brain, and studies using the Substance P antagonist, MK-869, have shown that it is likely to be important in the pathogenesis of depression. In addition, Substance P may be one of several neurotransmitters involved with circadian rhythms. L-759274 is a potent and highly selective non-peptide NK1 receptor antagonist with a long duration of action in preclinical models. It is 3000-fold selective for the human NK1 receptor versus the human NK3 receptor, and >20,000-fold selective versus the human NK2 and other G-protein coupled receptors and ion channels that have been tested. L-759274 acts as a competitive antagonist of Substance P from at human NK1 receptors as it has no effect on the rate of dissociation of Substance P from this receptor but reduces the apparent affinity of the receptor for [1251]-Substance P.
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