GR 64349, A Selective and Potent NK2 Agonist

2018-09-21

Introduction 

GR 64349 is a selective and potent NK2 agonist (EC50 = 3.7 nM in rat colon) with activity comparable to that of neurokinin A (NKA). Besides, it displays > 1000- and > 300-fold selectivity over NK1 and NK3 receptors, respectively. And it's active in vivo.

Pharmacologic action

It is possible that the antagonism of the NK1 mediated effects somehow altered the effectiveness of the tonic NK2 receptor mediated component, since the effects of the NK1 antagonists were similar to those of the NK2 agonist, GR 64349. There are two possible explanations for it. Firstly, either the antagonists or the agonists may not be selective. Secondly, NK1 receptors are more abundant in the dorsal horn than NK2 receptors. Therefore, synaptically released substance P (SP) and neurokinin A (NKA) (which are not particularly selective between NK1 and NK2 receptors) will be more likely to act via the more abundant NK1 receptors. And blocking this NK1 effect could allow a weaker NK2 mediated component to become more prominent. The second possibility is considered to be more likely.

Function

GR 64349 has proved to be a valuable pharmacological tool since it exhibits increased resistance to peptidases in biological preparations when compared with NKA, in addition to its high selectivity (> 1000-fold) over NK1 receptors. The experiments show that many agonists caused bradycardia, but GR 64349 was the most effective one (34 ± 4% decrease in heart rate with 32 nmol, n = 8). The prominent increases in ventricular contractility and perfusion pressure also occurred with 32 nmol of GR 64349 (25 ± 6 and 33 ± 4%, respectively). Desensitization with GR 64349 reduced the bradycardic response to NKA by greater than 75% and eliminated the positive inotropic response. The remaining bradycardia occurred through NK3 receptors. Negative chronotropic responses to NKA were reduced by 82% after desensitization with GR 64349.

Pharmacokinetics and metabolism

GR 64349 caused a dose-dependent increase in perfusion pressure (ED50 = 0.95 nmol). And a depressor response preceded the pressor effect of GR 64349 at doses of 10 and 32 nmol.

References:

1. B. A. Chizh, M. J. Cumberbatch, P. J. Birch and P. MaxHeadley. Endogenous modulation of excitatory amino acid responsiveness by tachykinin NK1 and NK2 receptors in the rat spinal cord. Br. J. Pharmacol., 1995, 115(6), 1013-1019.

2. M. J. Deal, R. M. Hagan, S. J. Ireland, C. C. Jordan, A. B. McElroy, B. Porter, B. C. Ross, M. Stephens-Smith and P. Ward. Conformationally constrained tachykinin analogs: potent and highly selective neurokinin NK-2 receptor agonists. J. Med. Chem., 1992, 35(22), 4195-4204.

3. Y. Chang, D. B. Hoover, J. C. Hancock and F. M. Smith. Tachykinin receptor subtypes in the isolated guinea pig heart and their role in mediating responses to neurokinin A. J. Pharmacol. Exp. Ther., 2000, 294(1), 147-154.

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