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MD Hollenberg, AA Laniyonu, M Saifeddine and GJ Moore
Department of Pharmacology and Therapeutics, University of Calgary, Faculty of Medicine, Alberta, Canada.
Using guinea pig gastric longitudinal muscle (GLM) and rat gastric longitudinal muscle (RLM) contractile assays and a rat aortic ring (RA) endothelium-dependent relaxation assay, we have examined the biological activities of a number of human and rat thrombin receptor-derived polypeptides (TRPs) modified at amino-terminal and carboxyl-terminal residues. Our study focused primarily on the human pentapeptide [S42FLLR46 (P5)], previously shown to retain full thrombin-like activity. Whereas N-acetylation (N-acetyl-P5) abolished biological activity in the GLM and RA assays, amidation or esterification of the carboxyl-terminal carboxyl group [P5-NH2, P5-OCH3, or S42FLLRNP48-NH2 (P7-NH2)] enhanced peptide potency by about 10-fold in both the GLM and RA assays, compared with the unmodified TRPs (P5 and P7). Removal from P5 of either the amino-terminal hydroxyl group of serine (to yield A42FLLR46) or both the amino-terminal hydroxyl group and the primary amino group of P5 [to yield propionyl-F43LLR46 (Pr-P4)] produced peptides that were active in both the GLM and RA assays. Substitution of the carboxyl-terminal guanidinium group of P5 with a less basic primary amino acid residue (S42FLLK46) resulted in a peptide with a lower potency than that of P5 in the GLM and RA assays, whereas substitution of D-arginine for L-arginine at the carboxyl terminus abolished biological activity. Substitution of norleucine for arginine (S42FLLNorleuN) resulted in a peptide active in the GLM but not in the RA assay. For selected agonists (Pr-P4, P5, P7, and P7-NH2), the potencies in the GLM and RA assays, relative to that of P5, differed; for the GLM the order was P7-NH2 > P7 > P5 congruent to Pr-P4, whereas for the RA the order was P7-NH2 > or = Pr-P4 >> P5 > or = P7. Data comparable to those obtained with the GLM assay were also obtained with a RLM assay, wherein the potency series was P7-NH2 > P7 > P5. The relative potencies of pentapeptides based on the rat receptor sequence [SFFLR (Ra-P5), SFFLR-NH2 (Ra-P5-NH2), and SFFLRNP (Ra-P7)] differed in the RLM and RA assays. In the RLM the order was Ra-P5-NH2 > P7-NH2 > P5- NH2 > Ra-P7 = P7 > P5 = Ra-P5, whereas in the RA the relative potency series was P7-NH2 > P5-NH2 > Ra-P5-NH2 > Ra-P7 > P5 > or = P7 > Ra- P5.(ABSTRACT TRUNCATED AT 400 WORDS)
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