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U-ll[5-11]NH2

30.2 ± 2.30

18.1 ±6.71

183 ±48

Table 2. Activity of truncated and amidated hU-ll octapeptides

Table 2. Activity of truncated and amidated hU-ll octapeptides

A recent report on the structural requirements of the N-terminus of amidated hU-ll octapeptides [4-11] has shown some interesting requirements for the Asp4 residue (Table 3). Removal of this residue altogether (U-ll[5-11]NH2) results in a substantial reduction in potency and affinity (27). The amino group on Asp was not required as evidenced by the high potency observed with the succinyl analog 6. Asp replacements in which the carboxylic acid functionality was differently displayed were also high affinity and potency compounds. Interestingly, however, whilst the fumaric acid derived amide 8 was equipotent at both human and rat receptors, the corresponding maleic acid amide 9 was able to distinguish between UT orthologs showing a much lower affinity for the rat receptor and ultimately resulting in a reduction in potency in the functional rat aorta ring contraction assay. Conversion of the Asp4 residue to an Asn resulted in retention of affinity and potency indicating that acidity per se was not necessary. Lastly, the hydrocarbon derivative 12 had only modest activity suggesting that a group with the capability of being a H-bond acceptor was preferred.

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