Neurokinin-3 receptor antagonists

Abstract

Until late 1994, research on the neurokinin-3 (NK 3 ) 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 NK 3 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 NK 3 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 NK 3 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.

Activation of the cloned human NK3 receptor in Chinese Hamster Ovary cells characterized by the cellular acidification response using the Cytosensor microphysiometer

“…Indeed, in the present study PD161182, PD168001 and PD168073 were all competitive antagonists as the slope factors yielded by their Schild analyses were not signi®cantly dierent from unity. Furthermore, the pA 2 values for these compounds, especially PD168073, compared favourably with the pA 2 value for the NK 3 antagonist SR142801 obtained in the current investigation, as well as with those previously reported for SR142801 using conventional assays Oury-Donat et al, 1995;Beaujouan et al, 1997) and with the new class of 2phenyl-4-quinolinecarboxamide derived NK 3 antagonists discovered by SmithKline Beecham (Giardina et al, 1996;Giardina & Raveglia, 1997). It is also worth noting that SR142801 is reported to antagonize dierentially senktide-and [MePhe 7 ]NKB-induced responses in the rabbit iris, suggesting that there may be subtypes of the NK 3 receptor .…”

“…For example, both GR138676 (Stables et al , 1994) and SR48968 (Petitet et al , 1993) are NK 3 antagonists with moderate affinity, but have little/no selectivity over NK 1 or NK 2 receptors respectively (Stables et al , 1994; Petitet et al , 1994). However, in the present study we have demonstrated that the novel compounds PD156319‐121, PD161182, PD168001 and PD168073, derived from our earlier chemical leads (Boden et al , 1994, Giardina & Raveglia, 1997), are all antagonists of high affinity against the senktide‐induced acidification response. In addition, these values are consistent with those obtained from the radioligand binding studies (Pritchard & Boden, 1995; Table 2), that also confirmed that these agents were selective for the NK 3 receptor (Pritchard & Boden, 1995 and results section).…”

Neuropeptide Receptors in Pain Circuitries: Useful Targets for CNS Imaging with Non-Peptide Ligands Suitable for PET?

“…The family of tachykinins includes in humans ten compounds of which eight share the carboxy terminal sequence F-X-G-L-M (X stands either for an aromatic amino acid or a ß-aliphatic amino acid) [178]- [180]: substance P (SP), neurokinin A (NK-A also called substance K), neurokinin B (NK-B also called neuromedin K) [181], neuropeptide K (NP-K), neuropeptide γ (NPG) [181]- [183] and human hemokinin-1 [184] belonging like EKA, B, C and EKD to the group of endokinins [179] [185]. The number of a. a.rs of these tachykinins has been found to be between 10 -36.…”

Synaptic mechanisms in nociception: emerging targets for centrally-acting analgesics

“…Clearly, investigations on NK 3 receptor antagonists as antihyperalgesic agents are in their very early stages, but the foregoing discussion indicates that there are several reasons for wishing to study them further. Sanofi [141], SmithKline Beecham [142] and Merck, Sharp & Dohme [143] have all reported selective, non-peptide NK 3 receptor antagonists that could form the basis for the development of therapeutically useful compounds (see [144]). …”