Add time:09/08/2019         Source:sciencedirect.com

A structure-activity study of the neurokinin A (NKA) fragment NKA(4–10) was performed to investigate the importance of amino acid residues for receptor efficacy, potency and affinity at the NK2 receptor in human colon circular muscle. Fourteen analogs of NKA(4–10) were produced with substitutions at positions 4, 5, 7, 9 and/or 10 of NKA. Their potencies were determined by in vitro contractile responses and affinities by radioligand binding using [125I]NKA. Functional potency was enhanced 8-fold by single amino acid substitutions with Lys5 and MeLeu9 but not significantly altered by substitutions Glu4, Arg5, His5 and Nle10. The multiply-substituted analogs [MeLeu9,Nle10]NKA(4–10), [Lys5,MeLeu9,Nle10]NKA(4–10) and [Lys5,(Tyr7),MeLeu9,Nle10]NKA(4–10) displayed 6–9-fold increase in potency. Although [Arg5,Nle10]NKA(4–10) was similar in potency to NKA(4–10), it was the only analog to show significantly reduced efficacy. All analogs were able to compete fully for [125I]NKA binding. [Lys5,MeLeu9]NKA(4–10), [MeLeu9,Nle10]NKA(4–10), [Lys5,Nle10]NKA(4–10) and analogs containing single substitutions with Glu4, Arg5, Lys5 and MeLeu9 displayed significantly higher affinity, whereas those with Nle10 and [Glu4,Nle10] substitutions showed significantly lower affinity than NKA(4–10). There was a positive correlation (r=0.63) between binding affinity and functional potency, which was markedly improved (r=0.95) by removal of three analogs: [Lys5,MeLeu9,Nle10]NKA(4–10), [Lys5,Tyr7,MeLeu9,Nle10]NKA(4–10) and [Lys5,Tyr(I2)7,MeLeu9,Nle10]NKA(4–10). These exhibited similar binding affinities to that of NKA(4–10) but were more potent in functional studies, possibly indicating a different mechanism of receptor interaction. In conclusion, substitution of Ser5 with Lys, and/or N-methylation of Leu9, were the most effective changes to increase functional and binding potency of NKA(4–10) at the human colon NK2 receptor.

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