Role of C-terminal amidation on the biological activity of neurokinin A derivatives with agonist and antagonist properties
Patacchini, R.; Quartara, L.; Rovero, P.; Goso, C.; Maggi, C.A.
Journal of Pharmacology and Experimental Therapeutics 264(1): 17-21
1993
ISSN/ISBN: 0022-3565 PMID: 8380857 Document Number: 412519
The mammalian tachykinins, neurokinin A (NKA) and NKA(4-10), along with the tachykinin NK-2 receptor-selective antagonist MEN 10,376, were compared to their C-terminal free acid acid derivatives, NKA-OH, NKA(4-10)-OH and MEN 10,456, respectively, on several in vitro bioassays for NK-1, NK-2 and NK-3 tachykinin receptors. NKA-OH and NKA(4-10)-OH were much weaker agonists than NKA or NKA(4-10) in the endothelium-deprived rabbit pulmonary artery (endowed with NK-2A receptors) and in the guinea pig isolated bronchus (endowed with NK-2A and NK-1 receptors), where they produced submaximal contractile responses, and were inactive in the hamster isolated trachea (endowed with NK-2B receptors) and in the rat isolated portal vein (endowed with NK-3 receptors). At NK-1 receptors of the guinea pig isolated ileum, NKA-OH produced weak agonist responses, whereas NKA(4-10)-OH was ineffective. In sharp contrast, MEN 10,456, while maintaining the same antagonist potency of the parent compound MEN 10,376 in the rabbit pulmonary artery and hamster isolated trachea, developed a clear-cut agonist character in the rat isolated portal vein, guinea pig isolated ileum and guinea pig isolated bronchus. The agonist responses produced by MEN 10,456 (10 mu-M) were reduced by MEN 10,376 in the guinea pig isolated bronchus and by the NK-1 receptor antagonist GR 82,334 in the guinea pig isolated ileum. These results, although indicating the importance of C-terminal amidation for the agonist activity of natural tachykinins, suggest that the C-terminal amide group may not be directly involved in stimulation of the tachykinin receptors, but could induce agonist activity through a conformational effect.