Single diastereomeric desaminotyrosylalanyl tetra- and heptapeptides with opioid antagonistic activity.
The N-terminal dipeptide Tyr-d-Ala of a mu-selective agonist, dermorphin tetrapeptide (DT, H-Tyr-D-Ala-Phe-Gly-NH2) and delta-selective agonist deltorphin C (DEL-C, H-Tyr-D-Ala-Phe-Asp-Val-Val- Gly-NH2) was changed into an aminodiacyl moiety. The relevant synthetic step is a nucleophilic substitution of bromine from a chiral 2-bromopropanamide by the amino group of tyrosine, with overall retention of configuration. The resulting pseudo tetra- and heptapeptides I-VI were characterized for mu- and delta-opioid receptor binding properties using [3H]DAGO and [3H]DPDPE, respectively, and in a bioassay using guinea pig ileum (GPI) and mouse vas deferens (MVD). As a result of chemical alteration of N-terminal depeptide moiety, all synthesized analogs showed considerable reduction in opioid receptor affinity compared to mu- and delta-prototypes (500-fold on the mu-site, analog I, and 125-fold on the delta-site, analog IV). Interestingly, analogs I and IV showed moderate antagonist activity, respectively, on GPI and MVD, with pA2 values of 6.05 and 6.82. Analog IV did not exhibit the delta-antagonist potency and delta-selectivity of TIPP peptides.
Balboni
G
G
Department of Pharmaceutical Science, University of Ferrara, Italy.
Salvadori
S
S
D'Angeli
F
F
Marchetti
P
P
Lazarus
L H
LH
Bryant
S D
SD
Bianchi
C
C
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D018847:Opioid Peptides; D011957:Receptors, Opioid / Q000378:metabolism*; D013237:Stereoisomerism; D044005:Tetrahydroisoquinolines; D014649:Vas Deferens / Q000378:metabolism
D004745:Enkephalins; D009292:Narcotic Antagonists; D009842:Oligopeptides; D018847:Opioid Peptides; D011957:Receptors, Opioid; D044005:Tetrahydroisoquinolines; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C059567:deltorphin; C082263:tyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-phenylalanyl-phenylalanine; C030058:dermorphin; D009020:Morphine; D020881:Enkephalin, D-Penicillamine (2,5)-