Replacement of the Tyr~1 Hydroxyl Group of TIPP Peptides with N-(Alky)carboxamido Groups Results in Potent and Selective δ Opioid Agonists or Antagonists

摘要

Substitution of a carboxamido (-CONH2) group for the Tyr~1 hydroxyl group in opioid peptides, as achieved by replacement of the tyrosine with ρ-carboxamidophenylalanine (Cpa), resulted in compounds that retained high opioid activity in vitro [1,2]. Replacement of the phenolic hydroxyl group in cyclazocine with a -CONH2 group had previously been shown to lead to a compound that also retained high μ receptor binding affinity [3]. Furthermore, introduction of a (4'-phenyl)-phenethyl substituent at the -CONH2 group of 8-carboxamido-cyclazocine resulted in a compound with unaltered μ receptor binding affinity [4]. Interestingly, a cyclic enkephalin analog containing 4'-[N-((4'-phenyl)-phenethyl)carboxamido]phenylalanine (Bcp; Figure 1) in place of Tyr~1, H-Bcp-c[D-Cys-Gly-Phe(ρNO2)-D-Cys]NH2, also showed high μ receptor binding affinity and turned out to be a potent, u-selective opioid agonist [5]. Here we describe analogs of the 8 opioid antagonists TIPP (H-Tyr-Tic-Phe-Phe-OH) and H-Tyr-Tic-OH, in which the Tyr residue was replaced by derivatives of Cpa containing various substituents at the pcarboxamido goup, including Bcp, 4'-[N-(hexyl)carboxamido]phenylalanine (Hep), 4'-[N-(2(naphthalen-2-yl)ethyl)carboxamido]phenylalanine (Ncp) and 2',6'-dimethyl-4'-[iV-((4'-phenyl)-phenethyl)carboxamido]phenylalanine (Dbcp) (Figure 1).