Stereospecificity of amino acid side chains in deltorphin defines binding to opioid receptors
摘要:
A series of individual D-amino acid replacement analogues of deltorphin A, several of which were in combination with a His4 deletion, were used to probe alterations of side-chain orientation on peptide binding parameters with rat brain opioid receptors. Peptides with D-amino acids in residues 1, 3, and 5 exhibited diminished affinities primarily for delta-receptors (88-1200-fold) with selectivity decreasing by factors of 13-64-fold relative to deltorphin A (K(i)delta = 0.45 nM; K(i)mu/K(i)delta = 764): the aromatic side chains Tyr1 and Phe3, which lie in the N-terminal "message" domain and the aryl side chain of Leu5 in the C-terminal "address" domain, appear to play essential roles in conferring high delta-affinity and selectivity. Although D-His4 only decreased delta-affinity by 6-fold and selectivity by a factor of 4, His appears to be involved as an integral component of both domains: [des-His4]deltorphin A and [des-His4] analogues containing consecutive D-amino acid replacements in the remaining residues exhibited weak binding to delta-receptors and poor delta-selectivity. Substitution of D-Met2 in deltorphin A by D-Ala or D-Nle decreased delta-selectivities 3-6-fold through an elevation in mu-affinities; however, the converse replacement, D-Met for D-Ala2 in deltorphin B, diminished beta-selectivity by an order of magnitude only through the loss in delta-affinity. The data show that the high delta-affinity and selectivity of deltorphins correlate with and require a strict stereospecificity of the amino acid residue side chains.
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DOI:
10.1021/jm00085a009
被引量:
年份:
1992
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