Systemic analgesic activity and .delta.-opioid selectivity in [2,6-dimethyl-Tyr1, D-Pen2, D-Pen5]enkephalin

Abstract

The cyclic peptide [2,6-dimethyl-Tyr1,D-Pen2,D-Pen5]enkephalin (2) was synthesized by solid-phase techniques and contains the optically pure unnatural amino acid 2,6-dimethyltyrosine (DMT) as a replacement for the Tyr1 residue of [D-Pen2,D-Pen5]enkephalin (DPDPE, 1). This structural modification resulted in a 10-fold increase in the potency of 2 at the delta opioid receptor and a 35-fold increase in potency at the mu receptor while substantial delta receptor selectivity was maintained. In addition, 2 was 86-fold more effective than 1 at inhibiting electrically stimulated contractions of the mouse vas deferens. In the hot plate test, 2 was 7-fold more potent than 1 after intracerebroventricular administration in the mouse. While 1 was inactive following systemic administration of doses as high as 30 mg/kg, subcutaneous administration of 2 significantly inhibited writhing with an ED50 of 2.6 mg/kg. These results demonstrate that the potency and systemic activity of DPDPE are significantly increased by replacement of Tyr1 with DMT.

2',6'-Dimethylphenylalanine (Dmp) Can Mimic the N-Terminal Tyr in Opioid Peptides

“…[2][3][4][5][6][7][8][9][10][11][12][13] However the Dmt 1 -substitution generally has resulted in low receptor selectivity due to markedly enhanced affinity toward the concomitant receptor vs. the preferred receptor. 3,6,8,12,13) We have recently demonstrated that 2Ј,6Ј-dimethylphenylalanine (Dmp) is an excellent surrogate for the Phe at position 3 in Tyr-D-Arg-Phe-bAla-NH 2 (YRFB), 14) endomorphin 2, 15) dermorphin, 16) and deltorphin II. 16) We also demonstrated that Dmp can be substituted for the N-terminal Tyr residue in the m receptor-selective agonists YRFB 14) and endomorphin 2 15) without a substantial decrease in m receptor affinity and selectivity.…”

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).…”

Development of neuropeptide drugs that cross the blood-brain barrier

“…Dimethylation of the N-terminal Tyr of DPDPE lead to a significant increase in analgesia. 61 In contrast, trimethylation of the Phe group of DPDPE significantly increased transport, without increasing analgesia. 62 Interestingly, this study of four different isomers of [Trimethyl-Phe 4 ] DPDPE showed differential effects on bioavailability, ligand-binding, and analgesia based solely on the methyl group position on the Phe benzene ring; only one isomer showed an increased transport, whereas the others had no effect, or decreased transport.…”