Preparation and opioid activities of N-methylated analogs of [D-Ala2,Leu5]enkephalin.
Analogs of opioid pentapeptide [D-Ala2,Leu5]enkephalin were prepared using two kinds of N-methylation reactions, namely quaternization and amide-methylation. Quaternization reaction with CH3I-KHCO3 in methanol was applied to the deprotected N-terminal group of the pentapeptide derivatives affording trimethylammonium group-containing analogs. [Me3+Tyr1,D-Ala2,Leu5]enkephalin and its amide were found to show opioid activity on guinea pig ileium assay only slightly lower than the parent unmethylated peptides. Application of amide-methylation reaction using CH3I-Ag2O in DMF to the protected pentapeptide yielded a pentamethyl derivative in which all of the five N atoms were methylated. Deprotection of the derivative gave pentamethyl analogs of [D-Ala2,Leu5]enkephalin, which showed no significant activity on the guinea pig ileum assay and opiate-receptor binding assay.
Kawai
M
M
Department of Applied Chemistry, Nagoya Institute of Technology, Japan.
Fukuta
N
N
Ito
N
N
Kagami
T
T
Butsugan
Y
Y
Maruyama
M
M
Kudo
Y
Y
D000595:Amino Acid Sequence; D000818:Animals; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008745:Methylation; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism
D011957:Receptors, Opioid; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine