Neurokinin-3 receptor antagonists

Abstract

Until late 1994, research on the neurokinin-3 (NK3) receptor, compared with that on neurokinin-1 (NK1) and neurokinin-2 (NK2) receptors, received little attention, due, to a large extent, to the absence of potent and selective non-peptide NK3 receptor antagonists. During 1995 and 1996, the disclosure of non-peptide antagonists led to a marked increase in research activities aimed at clarifying the physiological and pathophysiological role of the NK3 receptor. This review addresses the recent highlights and developments in this area, with particular emphasis on non-peptide NK3 receptor antagonists. Focus has been given to the various strategies utilised by several pharmaceutical companies to identify NK3 receptor antagonist prototypes and on the chemical optimisation processes which led to the potent and selective peptide-derived PD 161182 (8), the dichlorophenylalkylpiperidine SR 142,801 (9) and the quinoline derivative SB 223412 (27), which are representative compounds of the three distinct chemical classes of non-peptide NK3 receptor antagonists disclosed to date. The human NK3 (hNK3) receptor was cloned and stably expressed in 1992, and studies on the distribution in rodents and humans revealed that it is present in the central nervous system (CNS) and periphery. Based on receptor distribution and on the pharmacological effects of selective NK3 receptor agonists, a number of potential therapeutic indications for NK3 receptor antagonists are suggested, including CNS disturbances, pain and inflammation, pulmonary and skin diseases. Overall, although evidence indicates a noticeable increase in interest and research on NK3 receptors in the last few years, extensive additional medicinal chemistry and pharmacology studies, including preclinical and clinical evaluation of appropriate compounds from distinct structural classes, are required to delineate the pathophysiological role of NK3 receptors and to establish more firmly potential therapeutic utilities of potent and selective NK3 receptor antagonists.