Molecular cloning, mutations and effects of NK1 receptor antagonists reveal the human-like pharmacology of gerbil NK1 receptors

The gNK1R coding sequence displayed an overall 95% and 97% homology with hNK1R and rNK1R, respectively. The affinity of the NK1R-selective agonist 3H-SarMet SP for human and gerbil NK1R was similar (2.0 and 3.1 nM) but lower for rNK1R (12.4 nM). The rank order potency of the agonists for NK1R was SP ≥ ASMSP ≥ NKA ⋙ pro7NKB in all species. The NK1R antagonists, ZD6021 and CP99994, had comparable affinity and potency for gerbil and human NK1R, but were 1000-fold less potent for rNK1R. In contrast, RP67580 had comparable affinity and potency for all three species. Mutations in positions 116 and 290 did not affect agonist potency at the gNK1R while the potency of the antagonists ZD6021 and CP99994 were markedly decreased (10-20-fold). It is concluded that gNK1R has similar antagonist pharmacology as the human-like orthologue and that species differences in antagonist function depend on key residues in the coding sequence and antagonist structure.