Introduction
In the respiratory tract, there are tachykinin P (SP) and neurokinin A (NKA) in capsaicin-sensitive primary afferent neurons. Bradykinin has various effects such as bronchoconstriction, mucus secretion, and plasma spillover. It is related to the pathogenesis of asthma. Three tachykinin receptors (NKl, NK2, and NK3) have been identified that all recognize the common c-terminus of tachykinins. The NK2-selective antagonist, MDL 29,913, was a weak antagonist of NKA and NKA(4-10) analogue. The cyclic hexapeptide, MDL 29,913, can relax airway smooth muscle via mechanisms other than tachykinin antagonism.
Function
The NK2-selective antagonist, MDL 29,913, was a weak antagonist of NKA and NKA(4-10) analogue. At a concentration of 2 μM, it produced a small but significant shift in the response curve to NKA and a greater shift (8 fold) in the curve to NKA(4-10) analogue, but it had no effect on responses to Sar-SP. MDL 29,913 has high affinity and MEN 10207 has low affinity for [251]-NKA binding sites in hamster bladder membranes. Recent study reported that the relative potencies of NP-r and NKA in the human isolated bronchus, and have attempted to characterize the receptor(s) mediating contraction, using the novel antagonist MDL 29,913, shown to be highly selective for NK2 receptor subtypes in hamster urinary bladder. The NK2 antagonist MDL 29,913 produced no significant shift in either the NKA or NPγ response curve, nor did it affect the pD2 for NKA. At a 10-fold higher concentration (20pM), MDL 29,913 markedly antagonized NPγ-induced contractions, with a substantial depression of the response (38 + 9%; P < 0.01) to the highest concentration of NPγ used (3μM).
Application
MDL 29,913 is therefore a useful, soluble, and potent antagonist at "classical" NK2 receptors. In the human bronchus, MDL 29,913 was a weak antagonist of responses to NPγ and did not display competitive antagonism. MDL 29,913 has airway effects other than neurokinin a receptor antagonism which could explain its ability to delay dyspnea in a relatively nonspecific manner.
References:
Black et al (1992) Tachykinin receptors in rabbit airways - characterization by functional, autoradiographic and binding studies. Br.J.Pharmacol. 107 429. PMID: 1384914.
Maggi et al (1993) MEN 10,573 and MEN 10,612, novel cyclic pseudopeptides which are potent tachykinin NK-2 receptor antagonists. Regul.Pept. 47 151. PMID: 82434901.
