Analogs of the .delta. opioid receptor selective cyclic peptide [cyclic][2-D-penicillamine,5-D-penicillamine]-enkephalin: 2',6'-dimethyltyrosine and Gly3-Phe4 amide bond isostere substitutions

Abstract

In order to develop systemically-active opioid peptides, the delta-selective, opioid pentapeptide [D-Pen2,D-Pen5]-enkephalin (DPDPE) was modified by esterification and by substitution of 2',6'-dimethyltyrosine for tyrosine to yield 4. Compound 4 was on the order of 8- and 800-fold more active than DPDPE in both delta and mu opioid radioligand binding assays, respectively, in rat neural membrane suspensions. Compound 4 was considerably more potent than DPDPE at inhibiting contractions of electrically-stimulated mouse vas deferens in vitro, and this effect was very sensitive to naltrindole, a delta-selective opioid antagonist. These observations can be taken as indication that 4 exerts its effects through delta opioid receptors. This interpretation is supported by the finding that the EC50 value of 4 derived in the smooth muscle assay is very similar to that derived in NG108-15 neuroblastoma cells, a preparation devoid of mu receptors. Unlike DPDPE, 4 exhibited significant, naloxone-sensitive, antinociceptive activity when administered systemically, as measured by inhibition of phenylbenzquinone-induced stretching in mice (ED50 = 2.1 mg/kg). Compound 4 also displayed significant antinociceptive activity following systemic administration as measured by its action in mice to increase latencies for tail withdrawal from radiant heat (ED50 = 50 mg/kg). Compound 4 did not produce morphine-like discriminative stimulus effects in rats trained to discriminate 3.0 mg/kg morphine from vehicle at doses ranging from 30 to 120 mg/kg. This observation can be interpreted as indication that within this dosage range there is an absence of morphine-like subjective effects. Physical dependence, however, could be induced in mice at higher doses of 4 under a progressively-graded, 4-day dose regimen. Congeners of 4 with amide bond surrogates for the Gly-Phe amide bond (oxymethylene, trans-double bond, and bismethylene isosteres) in the cyclic core of DPDPE were prepared in an attempt to increase the antinociceptive activity of 4. While some of the congeners were active in the in vitro assays, they did not display significant antinociceptive activity following systemic administration. The preparation of all the compounds was accomplished by solution-phase methods. The mechanisms which might underlie the biological and systemic activity of 4 are discussed.

A Straightforward Synthesis of Six‐Membered‐Ring Heterocyclic α‐Aminophosphonic Acids from N‐Acyliminium Ions

“…High‐resolution FAB + and CI + mass spectra [high‐resolution mass spectrometry (HRMS)] were obtained on a JEOL MStation MS‐700. 1 H and 13 C NMR data for the compounds 13 – 15 and 5 were identical to those described in the literature.…”

Expression of EphB receptors and EphrinB ligands in the developing chick auditory brainstem

“…The development of a unique analogue of Tyr, achieved through methylation of the 2′ and 6′ positions of the tyramine ring to yield Dmt49 paved the way for realizing increased bioactivities in small opioid dipeptides. Whereas some substitutions of Dmt into [2‐ D ‐penicillamine, 5‐ D ‐penicillamine]‐enkephalin (DPDPE) and Dmt‐ N ‐(3‐phenylpropyl)‐ D ‐alaninamide did not yield dramatic results,50–53 the incorporation of Dmt into H–Tyr–Tic–OH increased δ‐receptor affinity 8500‐fold 54. This finding revolutionized the opioid field by clearly demonstrating that a single amino acid residue can have monumental effects on the opioid receptor affinity and bioactivity and firmly established the Dmt–Tic pharmacophore (Figure 1) as a new template for opioid ligand design 54, 55…”

Novel 2′,6′-Dimethyl-l-Tyrosine-Containing Pyrazinone Opioid Mimetic μ-Agonists with Potent Antinociceptive Activity in Mice

“…Later alterations in opioid structure, in particular the substitution of the N-terminal residue Tyr by Dmt (Chandrakumar et al, 1992;Hansen et al, 1992;Pitzele et al, 1994;Guerrini et al, 1996;Salvadori et al, 1997;Sasaki et al, 1999;Schiller et al, 2000;Bryant et al, 2003) and dimerization of Dmt through alkyldiamine , led to increases in the binding to opioid receptors and bioactivities in vitro and in vivo (Bryant et al, 2003). This study provided evidence that a pyrazinone ring connecting to two symmetric Dmt N termini by alkyl chains might serve a dual role in opioid peptides as both message and address domains.…”

“…Message and address domains of opioid peptides represent distinct starting points for the design and development of novel opioid mimetics. For example, studies on opioid peptides showed that the substitution of the N-terminal tyrosine by 2Ј,6Ј-dimethyl-L-tyrosine (Dmt) dramatically increased receptor affinity in numerous peptides and enhanced their antinociceptive effect (Chandrakumar et al, 1992;Hansen et al, 1992;Pitzele et al, 1994;Guerrini et al, 1996;Sasaki et al, 1999;Schiller et al, 2000;Bryant et al, 2003). Moreover, Dmt played a key role in the formation of the Dmt-Tic pharmacophore family of potent ␦-opioid receptor antagonists (Salvadori et al, 1997;Bryant et al, 1998, which were transformed into potent ␦-opioid receptor agonists by subtle changes in the C-terminal link to a third aromatic nucleus (Balboni et al, 2002).…”