Selective agonists for receptors of substance P and related neurokinins

Abstract

Neurokinins and their receptors are a complex system consisting of at least three endogenous agents--substance P (SP), neurokinin A (NKA), and neurokinin B (NKB)--and their corresponding receptor types, respectively, NK-1, NK-2, and NK-3. Investigations on receptors have been made using sensitive and fairly selective pharmacological preparations (the dog carotid artery for the NK-1, the rabbit pulmonary artery devoid of endothelium for the NK-2, and the rat portal vein for the NK-3 receptor), and some natural peptides of mammalian and nonmammalian origin. Because of the nonselectivity of the natural peptides, analogues of the neurokinins have been found that act on one receptor only and show therefore high selectivity. The selective agonists [Sar9,Met(O2)11]SP, [Nle10]NKA (4-10), and [MePhe7]-NKB have been used successfully for (a) characterizing the three neurokinin receptors, (b) identifying isolated organs whose responses to neurokinins depend on the activation of a single (monoreceptor systems) or of more than one (multireceptor systems) receptor, and (c) elucidating some of the physiological function of the three receptor types. It is suggested that NK-1 mediate peripheral vasodilatation and exocrine secretions, NK-2 stimulate bronchial muscles and facilitate the release of catecholamines, and NK-3 promote the release of acetylcholine in peripheral organs.

Recombinant bovine neurokinin-2 receptor stably expressed in Chinese hamster ovary cells couples to multiple signal transduction pathways.

“…[1251]NKA binding was displaced by NKA with an IC50 of 12.6 ± 1.6 nM (n = 3) and by naturally occurring neurokinins with the relative rank order of affinity NKA>NKB>SP (Figure 1). This rank order of displacement is consistent with radioligand binding to the NK-2 receptor subtype (Grandordy et al, 1988;Regoli et al, 1989 at 10-6 M stimulated a rapid 4.6 ± 0.6-fold (n = 3) increase in IP3 formation that was maximal at 1 min and thereafter declined to basal levels by 15-30 min ( Figure 2A). NKA displayed an EC50 of 125 ± 11 nM (n = 6) with maximal stimulation observed at 500 nM ( Figure 2B).…”

“…Another important regulator of phospholipases associated with arachidonic acid generation is PKC (Exton, 1990), and inhibition with staurosporine (1 jiM) suppressed substantially NKA- half-maximal effect observed at 1.4 ± 0.6 nM (n = 6) ( Figure 8A). (Grandordy et aL, 1988;Regoli et al, 1989). Moreover, NKA-stimulated IP3 generation in the CB/4 clone is consistent with similar observations in guinea pig trachea (Grandordy et al, 1988), whereas NK-2 receptor-mediated increases in de novo DNA synthesis has also been reported previously in thymocytes, smooth muscle cells, and skin fibroblasts (Nilsson etal., 1985;Soder and Hellstrom, 1989).…”

Binding and Functional Potency of Neurokinin A Analogues in the Rat Fundus: A Structure-Activity Study

“…In agreement with previous studies at NK-2 receptors in rat colon [22] and rabbit pulmonary artery [4], the binding affinity of NKA(4-10) was decreased 100-fold by replacement of Met 10 with Nle (data not shown). However, while the binding affinity of [Nle 10 ]NKA(4-10) is lower, other studies in rabbit isolated pulmonary artery have shown that the selectivity of this compound for the NK-2 receptor is improved [4,23,24].…”

CD,1H NMR and molecular modeling studies of the interaction of Ca2+ with substance P and Ala7-substance P in a non-polar solvent

“…We have, in our laboratory, regarded the interaction of the peptide hormone with extracellular Ca 2 + as an additional factor that would modify the conformation of the lipid-bound hormone [26]. That the Ca 2 + -bound structure is biologically relevant has been demonstrated by our showing a correlation between the activities of GnRH analogs and their extent of interaction with A large number of the structure-activity studies on SP are based on measurements on chemically modified forms of the parent hormone [44][45][46]. However, such studies tend to be empirical and do not provide a clue to the bioactive (receptor-bound) conformation of SP.…”