Structure-activity relationships of dermorphin analogues containing N-substituted amino acids in the 2-position of the peptide sequence.
A series of dermorphin analogues containing an N-alkylated amino-acid residue Xaa in the 2-position of the peptide sequence was synthesized (Xaa = N-methylalanine, proline, pipecolic acid, N-methylphenylalanine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid [Tic]). These peptides have the potential of assuming a cis Tyr1-Xaa2 peptide bond. Their in vitro opioid activity profiles were determined in mu- and delta-receptor-representative binding assays and bioassays. Aside from [D-Pro2]dermorphin, all analogues showed high affinity for mu- and/or delta-opioid receptors. Whereas most compounds were found to be full mu-agonists in the guinea pig ileum (GPI) assay, [Tic2]dermorphin (compound 7) was a partial mu-agonist. Replacement of Gly4 in 7 with Phe resulted in an analogue (8) with weak mu-antagonist activity. Furthermore, analogues 7 and 8 both were potent delta-antagonists (Ke = 3-40 nM) against the delta-agonists Leu-enkephalin, DPDPE and deltorphin I in the mouse vas deferens (MVD) assay. Compound 3, containing L-Pro in the 2-position, turned out to be one of the most mu-receptor-selective linear dermorphin analogues reported to date. Low-temperature HPLC experiments using micropellicular octadecyl silica as stationary phase revealed conformational heterogeneity of the dermorphin analogues which was ascribed to cis-trans isomerization around the Tyr1-Xaa2- and Tyr5-Pro6 peptide bonds. In the case of analogue 7 four separate peaks corresponding to the four possible isomers were apparent at -5 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)
Schmidt
R
R
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Quebec, Canada.
Kálmán
A
A
Chung
N N
NN
Lemieux
C
C
Horváth
C
C
Schiller
P W
PW
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D006168:Guinea Pigs; D007082:Ileum / Q000378:metabolism; D008297:Male; D008745:Methylation; D051379:Mice; D008969:Molecular Sequence Data; D009292:Narcotic Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018847:Opioid Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013696:Temperature; D014649:Vas Deferens / Q000378:metabolism
D009292:Narcotic Antagonists; D009842:Oligopeptides; D018847:Opioid Peptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C030058:dermorphin