Synthesis and biological evaluations of novel endomorphin analogues containing α-hydroxy-β-phenylalanine (AHPBA) displaying mixed μ/δ opioid receptor agonist and δ opioid receptor antagonist activities
European Journal of Medicinal Chemistry
α-Hydroxy-β-phenylalanine, Opioid receptors, Half-lives, MOR agonist/DOR agonist, MOR agonist/DOR antagonist
A novel series of endomorphin-1 (EM-1) and endomorphin-2 (EM-2) analogues was synthesized, incorporating chiral α-hydroxy-β-phenylalanine (AHPBA), and/or Dmt1-Tic2 at different positions. Pharmacological activity and metabolic stability of the series was assessed. Consistent with earlier studies of β-amino acid substitution into endomorphins, multiple analogues incorporation AHPBA displayed high affinity for μ and δ opioid receptors (MOR and DOR, respectively) in radioligand competition binding assays, and an increased stability in rat brain membrane homogenates, notably Dmt-Tic-(2R,3S)AHPBA-Phe-NH2 (compound 26). Intracerebroventricular (i.c.v.) administration of 26produced antinociception (ED50 value (and 95% confidence interval) = 1.98 (0.79–4.15) nmol, i.c.v.) in the mouse 55 °C warm-water tail-withdrawal assay, equivalent to morphine (2.35 (1.13–5.03) nmol, i.c.v.), but demonstrated DOR-selective antagonism in addition to non-selective opioid agonism. The antinociception of 26 was without locomotor activity or acute antinociceptivetolerance. This novel class of peptides adds to the potentially therapeutically relevant collection of previously reported EM analogues.
Hu, Miao; Giulianotti, Marc; McLaughlin, Jay P.; Shao, Jiaan; Debevec, Ginamarie; Maida, Laura E.; Geer, Phaedra; Cazares, Margaret; Misler, Jaime; Li, Ling; Dooley, Colette T.; Ganno, Michelle L.; Eans, Shainnel O. Torrey Pines Institute for Molecular Studies; Mizrachi, Elisa; Santos, Radleigh; Yongye, Austin B.; Houghten, Richard A.; and Yu, Yongping, "Synthesis and biological evaluations of novel endomorphin analogues containing α-hydroxy-β-phenylalanine (AHPBA) displaying mixed μ/δ opioid receptor agonist and δ opioid receptor antagonist activities" (2015). Mathematics Faculty Articles. 235.