title: Electronic, steric, and hydrophobic factors influencing the action of enkephalin-like peptides on opiate receptors.
abstract: The requirements of opiate receptors for electronic, steric, and hydrophobic properties of the amino acids in Pos. 4 and 5 of enkephalin-like peptides were studied. A series of [D-Ala2]-enkephalins containing carboranylalanine, adamantylalanine, t-butylglycine and p-nitrophenylalanine were synthesized and their pharmacological activities in the guinea pig ileum and their naloxone displacement in rat brain homogenates determined. An electronegative (-E) aromatic character of the amino acid in Pos. 4 strongly enhanced potency, overruling steric effects. The enhancement was not caused by exceptional enzyme resistance. Amino acid in Pos. 5 contributed to potency mainly through its effect on overall hydrophobicity. The two C-terminal amino acids seem to function as potentiator and address elements in the enkephalins.
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D010450:Endopeptidases; D004723:Endorphins / Q000494:pharmacology*; D004745:Enkephalins / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D009270:Naloxone / Q000378:metabolism; D011487:Protein Conformation; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D004723:Endorphins; D004745:Enkephalins; D011957:Receptors, Opioid; D009270:Naloxone; D010450:Endopeptidases