Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278080 (physical dependence)
 1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Opioid compounds with mixed mu agonist/delta antagonist properties are expected to be analgesics with low propensity to produce tolerance and dependence. In an effort to strengthen the mu agonist component of the mixed mu agonist/delta antagonist H-Tyr-Tic-Phe-Phe-NH(2) (TIPP-NH(2)), analogues containing structurally modified tyrosine residues in place of Tyr(1) were synthesized. Among the prepared compounds, H-Dmt-Tic-Phe-Phe-NH(2) (DIPP-NH(2); Dmt = 2',6'-dimethyltyrosine) and H-Dmt-TicPsi[CH(2)NH]Phe-Phe-NH(2) (DIPP-NH(2)[Psi]) retained a mixed mu agonist/delta antagonist profile, as determined in the guinea pig ileum and mouse vas deferens assays, whereas H-Tmt-Tic-Phe-Phe-NH(2) (Tmt = N,2',6'-trimethyltyrosine) was a partial mu agonist/delta antagonist and H-Tmt-TicPsi[CH(2)NH]Phe-Phe-NH(2) was a mu antagonist/delta antagonist. DIPP-NH(2)[Psi] showed binding affinities in the subnanomolar range for both mu and delta receptors in the rat brain membrane binding assays, thus representing the first example of a balanced mu agonist/delta antagonist with high potency. In the rat tail flick test, DIPP-NH(2)[Psi] given icv produced a potent analgesic effect (ED(50) = 0.04 microg), being about 3 times more potent than morphine (ED(50) = 0.11 microg). It produced less acute tolerance than morphine but still a certain level of chronic tolerance. Unlike morphine, DIPP-NH(2)[Psi] produced no physical dependence whatsoever upon chronic administration at high doses (up to 4.5 microg/h) over a 7-day period. In conclusion, DIPP-NH(2)[Psi] fulfills to a large extent the expectations based on the mixed mu agonist/delta antagonist concept with regard to analgesic activity and the development of tolerance and dependence.
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PMID:The opioid mu agonist/delta antagonist DIPP-NH(2)[Psi] produces a potent analgesic effect, no physical dependence, and less tolerance than morphine in rats. 1047 85

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).
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PMID:The TIPP opioid peptide family: development of delta antagonists, delta agonists, and mixed mu agonist/delta antagonists. 1079 30

Two recent developments of opioid peptide-based analgesics are reviewed. The first part of the review discusses the dermorphin-derived, cationic-aromatic tetrapeptide H-Dmt-D-Arg-Phe-Lys-NH(2) ([Dmt(1)]DALDA, where Dmt indicates 2',6'-dimethyltyrosine), which showed subnanomolar mu receptor binding affinity, extraordinary mu receptor selectivity, and high mu agonist potency in vitro. In vivo, [Dmt(1)]DALDA looked promising as a spinal analgesic because of its extraordinary antinociceptive effect (3000 times more potent than morphine) in the mouse tail-flick assay, long duration of action (4 times longer than morphine), and lack of effect on respiration. Unexpectedly, [Dmt(1)]DALDA also turned out to be a potent and long-acting analgesic in the tail-flick test when given subcutaneously (s.c.), indicating that it is capable of crossing the blood-brain barrier. Furthermore, little or no cross-tolerance was observed with s.c. [Dmt(1)]DALDA in morphine-tolerant mice. The second part of the review concerns the development of mixed mu agonist/delta antagonists that, on the basis of much evidence, are expected to be analgesics with a low propensity to produce tolerance and physical dependence. The prototype pseudopeptide H-Dmt-TicPsi[CH(2)NH]Phe-Phe-NH(2) (DIPP-NH(2)[Psi], where Tic indicates 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) showed subnanomolar mu and delta receptor binding affinities and the desired mu agonist/delta antagonist profile in vitro. DIPP-NH(2)[Psi] produced a potent analgesic effect after intracerebroventricular administration in the rat tail-flick assay, no physical dependence, and less tolerance than morphine. The results obtained with DIPP-NH(2)[Psi] indicate that mixed mu agonist/delta antagonists look promising as analgesic drug candidates, but compounds with this profile that are systemically active still need to be developed.
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PMID:Opioid peptide-derived analgesics. 1635 33