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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Substitution of Various p-N-AlkylcarboxamidophenylalanineAnalogues for Tyr 1 in TIPP Opioid PeptidesIrena Berezowska, Carole Lemieux, Nga N. Chung, andPeter W. SchillerLaboratory of Chemical Biology and Peptide Research, Clinical Research Institute ofMontreal, Montreal, Quebec, H2W 1R7, CanadaIntroductionReplacement of the Tyr 1 residue in the cyclic enkephalin analogue H-Tyr-c[D-Cys-Gly-Phe(pNO2)-D-Cys]NH 2 with 4'-[N-((4'-phenyl)-phenethyl)carboxamido]phenylalanine(Bcp) resulted in a highly potent, μ-selective opioid agonist [1]. Unexpectedly, an analogueof the δ opioid antagonist peptide TIPP (H-Tyr-Tic-Phe-Phe-OH); Tic = 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) [2] containing Bcp in place of Tyr 1 showedpotent δ opioid agonist activity [3]. To further explore structure-activity relationships ofTIPP at the N-terminal amino acid residue, derivatives of 4'-carboxamidophenylalanine(Cpa) containing various alkyl substituents at the 4'-carboxamido group were synthesizedand substituted for Tyr 1 . These include 4'-[N-(hexyl)carboxamido]phenylalanine (Hcp), 4'-[N-(decyl)carboxamido]phenylalanine (Dcap), 4'-[N-(diethyleneglycol)carboxamido]-phenylalanine (Dgcp) and 4'-[N-(methoxypolyethyleneglycol)carboxamido]phenylalanine(Mgcp) (Figure 1).Fig. 1. Structure of TIPP analogs.Fig. 2. Synthetic scheme.Materials and MethodsBoc-Phe(4`-COOH)-OMe was synthesized by activating the hydroxyl group of Boc-Tyr-OMe as the triflate, followed by carbonylation with carbon monoxide in the presence ofpotassium acetate, DPPF and palladium (II) acetate, as described by Wang et al. [4].Subsequent reactions with ammonium chloride, hexylamine, decylamine, diethyleneglycolamine or methoxypolyethylene glycol amine using HBTU as coupling agent,followed by ester hydrolysis with 2N NaOH yielded the target compounds (Figure 2).Peptides were synthesized on solid-phase. μ, δ and κ opioid receptor affinities weremeasured in binding assays based on displacement of μ-, δ- and κ-selective radioligands426