Discovery of a Potent and Efficacious Peptide Derivative for δ/μ Opioid Agonist/neurokinin 1 Antagonist Activity with a 2',6'-dimethyl-L-tyrosine: in Vitro, in Vivo, and NMR-based Structural Studies

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2011 Mar 4

PMID 21366266

Citations 14

Authors

Takashi Yamamoto

Padma Nair

Tally M Largent-Milnes

Neil E Jacobsen

Peg Davis

Shou-Wu Ma

Henry I Yamamura

Todd W Vanderah

Frank Porreca

Josephine Lai

Victor J Hruby

Affiliations

Soon will be listed here.

Abstract

Multivalent ligands with δ/μ opioid agonist and NK1 antagonist activities have shown promising analgesic potency without detectable sign of toxicities, including motor skill impairment and opioid-induced tolerance. To improve their biological activities and metabolic stability, structural optimization was performed on our peptide-derived lead compounds by introducing 2',6'-dimethyl-L-tyrosine (Dmt) instead of Tyr at the first position. The compound 7 (Dmt-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-[3',5'-(CF(3))(2)-Bzl]) showed improved multivalent bioactivities compared to those of the lead compounds, had more than 6 h half-life in rat plasma, and had significant antinociceptive efficacy in vivo. The NMR structural analysis suggested that Dmt(1) incorporation in compound 7 induces the structured conformation in the opioid pharmacophore (N-terminus) and simultaneously shifts the orientation of the NK1 pharmacophore (C-terminus), consistent with its affinities and activities at both opioid and NK1 receptors. These results indicate that compound 7 is a valuable research tool to seek a novel analgesic drug.

Citing Articles

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References

Yaksh T, Rudy T . Chronic catheterization of the spinal subarachnoid space. Physiol Behav. 1976; 17(6):1031-6. DOI: 10.1016/0031-9384(76)90029-9. View

Ripley T, Gadd C, de Felipe C, Hunt S, Stephens D . Lack of self-administration and behavioural sensitisation to morphine, but not cocaine, in mice lacking NK1 receptors. Neuropharmacology. 2003; 43(8):1258-68. DOI: 10.1016/s0028-3908(02)00295-2. View

DAlagni M, Delfini M, Di Nola A, Eisenberg M, Paci M, Roda L . Conformational study of [Met5]enkephalin-Arg-Phe in the presence of phosphatidylserine vesicles. Eur J Biochem. 1996; 240(3):540-9. DOI: 10.1111/j.1432-1033.1996.0540h.x. View

Largent-Milnes T, Yamamoto T, Nair P, Moulton J, Hruby V, Lai J . Spinal or systemic TY005, a peptidic opioid agonist/neurokinin 1 antagonist, attenuates pain with reduced tolerance. Br J Pharmacol. 2010; 161(5):986-1001. PMC: 2998681. DOI: 10.1111/j.1476-5381.2010.00824.x. View

Horan P, Mattia A, Bilsky E, Weber S, Davis T, Yamamura H . Antinociceptive profile of biphalin, a dimeric enkephalin analog. J Pharmacol Exp Ther. 1993; 265(3):1446-54. View

Kalso E . Improving opioid effectiveness: from ideas to evidence. Eur J Pain. 2005; 9(2):131-5. DOI: 10.1016/j.ejpain.2004.05.007. View

Weiner S, Kollman P, Nguyen D, Case D . An all atom force field for simulations of proteins and nucleic acids. J Comput Chem. 2017; 7(2):230-252. DOI: 10.1002/jcc.540070216. View

Wagner G, Neuhaus D, Worgotter E, Vasak M, KAGI J, Wuthrich K . Nuclear magnetic resonance identification of "half-turn" and 3(10)-helix secondary structure in rabbit liver metallothionein-2. J Mol Biol. 1986; 187(1):131-5. DOI: 10.1016/0022-2836(86)90413-4. View

Millet R, Goossens L, Goossens J, Chavatte P, Houssin R, Henichart J . Conformation of the tripeptide Cbz-Pro-Leu-Trp-OBzl(CF3)2 deduced from two-dimensional 1H-NMR and conformational energy calculations is related to its affinity for NK1-receptor. J Pept Sci. 2001; 7(6):323-30. DOI: 10.1002/psc.326. View

10.

Hokfelt T, Kellerth J, Nilsson G, PERNOW B . Experimental immunohistochemical studies on the localization and distribution of substance P in cat primary sensory neurons. Brain Res. 1975; 100(2):235-52. DOI: 10.1016/0006-8993(75)90481-3. View

11.

Jacobsen N, Abadi N, Sliwkowski M, Reilly D, Skelton N, Fairbrother W . High-resolution solution structure of the EGF-like domain of heregulin-alpha. Biochemistry. 1996; 35(11):3402-17. DOI: 10.1021/bi952626l. View

12.

Misterek K, Maszczynska I, Dorociak A, Gumulka S, Carr D, Szyfelbein S . Spinal co-administration of peptide substance P antagonist increases antinociceptive effect of the opioid peptide biphalin. Life Sci. 1994; 54(14):939-44. DOI: 10.1016/0024-3205(94)00494-3. View

13.

King T, Ossipov M, Vanderah T, Porreca F, Lai J . Is paradoxical pain induced by sustained opioid exposure an underlying mechanism of opioid antinociceptive tolerance?. Neurosignals. 2005; 14(4):194-205. DOI: 10.1159/000087658. View

14.

MacLeod A, Merchant K, Cascieri M, Sadowski S, Ber E, Swain C . N-acyl-L-tryptophan benzyl esters: potent substance P receptor antagonists. J Med Chem. 1993; 36(14):2044-5. DOI: 10.1021/jm00066a015. View

15.

Deber C, Behnam B . Role of membrane lipids in peptide hormone function: binding of enkephalins to micelles. Proc Natl Acad Sci U S A. 1984; 81(1):61-5. PMC: 344610. DOI: 10.1073/pnas.81.1.61. View

16.

Yamamoto T, Nair P, Jacobsen N, Davis P, Ma S, Navratilova E . The importance of micelle-bound states for the bioactivities of bifunctional peptide derivatives for delta/mu opioid receptor agonists and neurokinin 1 receptor antagonists. J Med Chem. 2008; 51(20):6334-47. PMC: 2675940. DOI: 10.1021/jm800389v. View

17.

Lee Y, Petrov R, Park C, Ma S, Davis P, Lai J . Development of novel enkephalin analogues that have enhanced opioid activities at both mu and delta opioid receptors. J Med Chem. 2007; 50(22):5528-32. PMC: 2678914. DOI: 10.1021/jm061465o. View

18.

Wishart D, Sykes B, Richards F . The chemical shift index: a fast and simple method for the assignment of protein secondary structure through NMR spectroscopy. Biochemistry. 1992; 31(6):1647-51. DOI: 10.1021/bi00121a010. View

19.

Yamamoto T, Nair P, Jacobsen N, Vagner J, Kulkarni V, Davis P . Improving metabolic stability by glycosylation: bifunctional peptide derivatives that are opioid receptor agonists and neurokinin 1 receptor antagonists. J Med Chem. 2010; 52(16):5164-75. PMC: 3521585. DOI: 10.1021/jm900473p. View

20.

Yamamoto T, Nair P, Ma S, Davis P, Yamamura H, Vanderah T . The biological activity and metabolic stability of peptidic bifunctional compounds that are opioid receptor agonists and neurokinin-1 receptor antagonists with a cystine moiety. Bioorg Med Chem. 2009; 17(20):7337-43. PMC: 2775479. DOI: 10.1016/j.bmc.2009.08.035. View