The biological consequences of replacing hydrophobic amino acids in deltorphin I with amphiphilic alpha-hydroxymethylamino acids.
New analogues of deltorphin I (DT I), in which the Phe residue in position 3, and the Val residue in position 5 or 6 are replaced with respective amphiphilic alpha-hydroxymethylamino acid residues (HmAA), were synthesized and tested for receptor affinity and selectivity to mu and delta opioid receptors. The analogue with (R)-HmPhe at position 3 lost receptor selectivity, as a result of a partial decrease of affinity to delta and a significant increase of affinity to mu receptors. In contrast, an analogue with (S)-HmPhe in the same position, was very potent and more specific to delta receptors than parent DT I. The analogue with (R)-HmVal at position 5 expressed higher delta affinity and selectivity than parent DT I. The analogue with other possible isomer (S)-HmVal was less selective for delta opioid receptors, as a result of decreasing affinity to delta and increasing affinity to mu receptors. The analogues with (R)- or (S)-HmVal in position 6 expressed equally low receptor affinity and selectivity. The data obtained support a previously proposed model of active conformation of deltorphins.
Olma
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Institute of Organic Chemistry, Technical University, 90-924 Łódź, Poland. olmaola@ck-sg.p.lodz.pl
Łachwa
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Lipkowski
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D019943:Amino Acid Substitution; D000596:Amino Acids / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D057927:Hydrophobic and Hydrophilic Interactions; D006900:Hydroxylation; D008745:Methylation; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D010649:Phenylalanine / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013501:Surface-Active Agents / Q000737:chemistry* / Q000378:metabolism; D014633:Valine / Q000737:chemistry / Q000378:metabolism
D000596:Amino Acids; D009842:Oligopeptides; D011957:Receptors, Opioid; D013501:Surface-Active Agents; C060208:deltorphin I, Ala(2)-; D010649:Phenylalanine; D014633:Valine