The TIPP opioid peptide family: development of delta antagonists, delta agonists, and mixed mu agonist/delta antagonists.
The discovery of the prototype delta opioid antagonists TIPP (H-Tyr-Tic-Phe-Phe-OH) and TIP (H-Tyr-Tic-Phe-OH) in 1992 was followed by extensive structure-activity relationship studies, leading to the development of analogues that are of interest as pharmacological tools or as potential therapeutic agents. Stable TIPP-derived delta opioid antagonists with subnanomolar delta receptor binding affinity and extraordinary delta receptor selectivity include TIPP[Psi] (H-Tyr-TicPsi[CH(2)NH]Phe-Phe-OH] and TICP[Psi] (H-Tyr-TicPsi[CH(2)NH]Cha-Phe-OH); Cha: cyclohexylalanine), which are widely used in opioid research. Theoretical conformational analyses in conjunction with the pharmacological characterization of conformationally constrained TIPP analogues led to a definitive model of the receptor-bound conformation of H-Tyr-Tic-(Phe-Phe)-OH-related delta opioid antagonists, which is characterized by all-trans peptide bonds. Further structure-activity studies revealed that the delta antagonist vs delta agonist behavior of TIP(P)-derived compounds depended on very subtle structural differences in diverse locations of the molecule and suggested a delta receptor model involving a number of different inactive receptor conformations. A further outcome of these studies was the identification of a new class of potent and very selective dipeptide delta agonists of the general formula H-Tyr-Tic-NH-X (X = arylalkyl), which are of interest for drug development because of their low molecular weight and lipophilic character. Most interestingly, TIPP analogues containing a C-terminal carboxamide group displayed a mixed mu agonist/delta antagonist profile, and thus were expected to be analgesics with a low propensity to produce tolerance and physical dependence. This turned out to be the case with the TIPP-derived mu agonist/delta antagonist DIPP-NH(2)[Psi] (H-Dmt-TicPsi[CH(2)NH]Phe-Phe-NH(2)); Dmt: 2',6'- dimethyltyrosine).
Schiller
P W
PW
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Quebec, Canada.
Weltrowska
G
G
Berezowska
I
I
Nguyen
T M
TM
Wilkes
B C
BC
Lemieux
C
C
Chung
N N
NN
D008958:Models, Molecular; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D018847:Opioid Peptides / Q000138:chemical synthesis* / Q000494:pharmacology; D011487:Protein Conformation; D011957:Receptors, Opioid / Q000819:agonists; D044005:Tetrahydroisoquinolines
D009292:Narcotic Antagonists; D009842:Oligopeptides; D018847:Opioid Peptides; D011957:Receptors, Opioid; D044005:Tetrahydroisoquinolines; C116539:tyrosyl-1,2,3,4-tetrahydro--3-isoquinolinecarbonyl-phenylalanyl-phenylalaninamide; C082263:tyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-phenylalanyl-phenylalanine