Bifunctional 2’6’-Dimethyl-l-tyrosine1Endomorphin-2 Analogues Substituted at Position 3 with Alkylated Phenylalanine Derivatives Yield Potent Mixed μ-Agonist/δ-Antagonist and Dual μ-/δ-Agonist Opioid Ligands

摘要

Endomorphin-2 (H-Tyr-Pro-Phe-Phe-NH2) and [Dmt¹]EM-2 (Dmt = 2’,6’-dimethyl-l-tyrosine) analogues were synthesized containing alkylated Phe³ derivatives, 2’-monomethyl (>2, >2’), 3’,5’- and 2’,6’-dimethyl (>3, >3’, and >4’, respectively), 2’,4’,6’-trimethyl (>6, >6’), 2’-ethyl-6’-methyl (>7, >7’) and 2’-isopropyl-6’-methyl (>8, >8’) groups or Dmt (>5, >5’). They had the following characteristics: (i) [Xaa³]EM-2 analogues improved μ- and δ-opioid receptor affinities, the latter were inconsequential (Ki^δ= 491–3,451 nM); (ii) [Dmt¹,Xaa³]EM-2 analogues enhanced μ- and δ-opioid receptor affinities (Ki^μ = 0.069–0.32 nM; Ki^δ = 1.83–99.8 nM) and lacked interaction with κ-opioid receptors, and (iii) elevated μ-bioactivity (IC50 = 0.12–14.4 nM) and abolished δ-agonism (IC50 > 10 µM; >2’, 3’, 4’, 5’, 6’); however, >4’ and >6’ exhibited mixed μ-agonism/δ-antagonism (>4’: IC50^μ = 0.12, pA2 = 8.15; >6’: IC50^μ = 0.21 nM, pA2 = 9.05), and >7’ was a dual μ-/δ -agonist (IC50^μ = 0.17 nM; IC50^δ = 0.51 nM). Alteration of EM-2 activity by Dmt¹ and alkylated Phe³ residues retained μ-receptor bioactivity and formed dual μ-/δ -agonists and mixed μ-agonists/δ-antagonists.