ABSTRACT: The present study investigates the pharmacology of the cloned neurokinin 1 receptor from the gerbil (gNK1R), a species claimed to have human-like NK1R (hNK1R) pharmacology.The amino acid sequence of NK1R was cloned. The hNK1R, rat NK1R (rNK1R), gNK1R and mutants of the gNK1R were expressed in CHO cells. The affinity and potency of NKR agonists and the NK1R antagonists CP99994 and RP67580 (NK1R-selective) and ZD6021 (NK1/2R) were assessed in vitro by monitoring [H]-SarMet SP binding and substance P-evoked mobilization of intracellular Ca. The gerbil foot tap (GFT) method was used to assess the potency of the antagonists in vivo.The gNK1R coding sequence displayed an overall 95% and 97% homology with hNK1R and rNK1R, respectively. The affinity of the NK1R-selective agonist H-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.(Figure is included in full-text article.)