Sensory and Inflammatory Peptide Receptors in Airways
Devendra K. Agrawal, Robert G. Townley in Inflammatory Cells and Mediators in Bronchial Asthma, 2020
Tachykinins produce their effects by interacting with specific surface receptors. Using several tachykinins it is possible to define different patterns of response, suggesting the existence of subtypes of tachykinin receptor. Thus, some tissues were shown to respond most to SP and physalaemin (from amphibia), but not to eledoisin, and these receptors were classified as SP-P receptors. In other tissues, eledoisin (derived from octopus) was more potent than SP and the receptor was therefore termed an SP-E receptor.14 NKA and neuropeptide K are also potent at these receptors, which are now classified as NK2 receptors, in contrast to NK1 receptors, which correspond to SP-P receptors (Figure 1). NKB, by contrast, is more potent at NK3 receptors.15,16 Recently, a fourth type of receptor (NK4) has been proposed based on the unique rank order of potency of newly synthesized tachykinin agonists in guinea pig trachea.17 No endogenous tachykinin which selectively activates this receptor has yet been described. Selective antagonists which discriminate the receptors are not yet available. Recently, the NK2 receptor has been cloned and expressed,18 and the use of cDNA probes for tachykinin receptor subtypes should make it easier to identify which receptor subtype each cell expresses.
Non Adrenergic, Noncholinergic Innervation of Gastrointestinal Vessels
Geoffrey Burnstock, Susan G. Griffith in Nonadrenergic Innervation of Blood Vessels, 2019
In pharmacological doses, SP has been reported to have vasoconstrictive actions as demonstrated in vitro in the inferior mesenteric or portal veins of the rat.57 Comparative studies in vitro on the vasodilator response of gastrointestinal peptides on mesenteric vessels generally showed more pronounced effects of arteries than of veins, with the exception of SP, which caused equipotent responses in both types of vessels.58 SP is also a potent liberator of histamine from mucosal mast cells.59 The vasodilator effects of SP in some vascular beds were reduced after pretreatment with antihistamines, which may indicate a partly indirect mode of action of SP.60 SP receptors have been suggested to be located on the endothelium, which seems to be a prerequisite for mediation of the dilatory responses.61 In vitro studies on the direct action of SP on smooth muscle indicate that SP has in fact indirect effects in most test systems, except in the rabbit mesenteric vein. The SP response in this tissue was unchanged after removal of the endothelium, or after blockade of cholinergic and histami-nergic receptors in combination with inhibition of prostaglandin synthesis.62,63 This vessel had also a characteristic pattern of response with regard to activation of subtypes of tachykinin receptors; the sensitivity to kassinin/eledoisin was higher than to physalaemin/SP.63,64 Studies on the vasodilatory actions of bradykinin have indicated that this peptide may act indirectly by the release of SP, since its actions were partly antagonized by SP analogues.65
Enzymatic Syntheses of Biologically Active Peptides
Willi Kullmann in Enzymatic Peptide Synthesis, 1987
A combination of enzymatic and chemical steps was used for the preparation of a protected eledoisin6-11-hexapeptide (Figure 12).50 However, in contrast to the previously mentioned syntheses of biological peptides or peptide fragments, the authors performed the enzymatic reactions in aqueous-organic biphasic systems. α-Chymotrypsin- and papain-catalyzed syntheses were enhanced both by the use of “preactivated” esterified acyl-group donors and by the precipitation of the resulting products. Furthermore, the extent of synthesis was markedly improved by using a twofold molar excess of the respective amine component. The biphasic systems which were composed of either a papain- or a chymotrypsin-specific buffer and carbon tetrachloride were chosen in order to favor the precipitation of the prospective products. Other work showed that the reaction yields were drastically diminished when a water-immiscible trichloroethylene/petroleum ether mixture or the water-miscible methanol were used in place of carbon tetrachloride. Yet, the degree of synthesis was not solely dependent on the chemical nature of the organic layer but was also affected by the volume ratio of the two phases. In the presence of chymotrypsin the hexapeptide Boc-Ala-Phe-Ile-Gly-Leu-Met-NH2 was obtained in maximum yield from its constituent di- and tetrapeptide (cf. Figure 12) only when carbon tetrachloride formed 60% by volume of the solvent system. Any increase or decrease in this figure resulted in reduced yields. Starting from the same educts, the eledoisin hexapeptide could also be obtained via papain catalysis (Figure 12). Unlike the chymotryptic synthesis, the optimal volume ratio of organic to aqueous phase amounted to 40 to 50% in the presence of papain. An alternative, synthetic route to the eledoisin hexapeptide involved the papain-catalyzed condensation of two tripeptide fragments (cf. Figure 12). In this case, however, the reaction yields remained unchanged when the percentage of organic co-solvent (CCl4) was increased from 10 to 50%.
Neurokinin receptor antagonism: a patent review (2014-present)
Published in Expert Opinion on Therapeutic Patents, 2020
Substance P (SP), hemokinin-1, neurokinin A (NKA), neurokinin B (NKB), neuropeptide K, eledoisin, ranakinin, and kassinin belong to the tachykinin family of peptides which, via the metabotropic neurokinin (NK)-1, NK-2 and NK-3 receptors, exert many physiological actions and are involved in many pathophysiological mechanisms (e.g. cancer, emesis, anxiety, depression, pain, alcohol addiction, inflammation, viral and bacterial infection, pruritus) [1–3].
Related Knowledge Centers
- Neuropeptide
- Peptide
- Smooth Muscle
- Substance P
- Hypertension
- Vasodilation
- Salivary Gland
- Tachykinin Peptides
- Kassinin
- Physalaemin