The Opioid μ Agonist/δ Antagonist DIPP-NH₂[Ψ] Produces a Potent Analgesic Effect, No Physical Dependence, and Less Tolerance than Morphine in Rats

Abstract

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.

Molecular Pharmacology ofδ-Opioid Receptors

“…The crystal structure of the human DOPr in complex with the mixed MOPr agonist/DOPr antagonist H-DmtTic-Phe-Phe-NH 2 (DIPP-NH 2 ; Dmt is 29,69-dimethyltyrosine and Tic is 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) (Schiller et al, 1999a) (described in section IV.D.1) at 2.7-Å resolution was recently determined by serial femtosecond crystallography using an X-ray free electron laser (Fenalti et al, 2015). Thus, for the first time, the crystal structures of a GPCR bound to a peptide ligand and to a d-Opioid Receptor Pharmacology nonpeptide ligand are now known.…”

Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series

“…Subsequent studies by using antisense oligodeoxynucleotides (8,9) and ␦ opioid receptor knockout mice (10) have supported these ideas, implicating -␦ interactions in the development of morphine tolerance and physical dependence. More recently, mixed agonist͞␦ antagonist ligands have been designed as an approach to analgesics devoid of these side effects (11)(12)(13).…”

Opioid ligands with mixed μ/δ opioid receptor interactions: An emerging approach to novel analgesics

“…When administered icv, DIPP-NH 2 [ ] produced a potent antinociceptive effect in the rat tail-fl ick test and produced less tolerance than morphine and no physical dependence on chronic administration at high dose levels, thus fulfi lling to a large extent the expectations based on the mixed agonist/ ␦ antagonist concept with regard to analgesic activity and development of tolerance and dependence. 53 Recently, chimeric peptides containing a agonist fragment and ␦ antagonist fragment have also been synthesized and evaluated. The chimeric peptide resulting from linking the agonist H-Dmt-D-Arg-Phe-Lys-NH 2 ([Dmt 1 ]DALDA) and the ␦ antagonist H-Tyr-Tic [CH 2 -NH]Cha-Phe-OH (TICP[ ]) (Cha = cyclohexylalanine) tail-to-tail using H 2 N-CH 2 -CH 2 -NH 2 as the linker has been shown to display the expected agonist/ ␦ antagonist profi le in the GPI and MVD bioassays.…”