Opioid Peptidleri: Farmasötik Açıdan Önemi ve Formülasyon Yaklaşımları

Opioidler, kendi reseptörlerine bağlanarak gösterdikleri ağrı kesici etki nedeniyle, binlerce yıldır ağrı tedavisinde kullanılmaktadır. Günümüzde kullanımları daha kontrollü olarak hala devam etmektedir. Ancak yan etkileri ve bağımlılık potansiyelleri nedeniyle hastaların izlenmesi gerekmektedir. Araştırmacılar tarafından, insan vücudunda doğal olarak sentezlenen ve opioid benzeri etkilere yol açan endojen opioid peptidleri bulunmuştur. Bu peptidlerin sentetik analogları da sentezlenmektedir. Bu bileşikler kimyasal yapılarından dolayı hidrofiliktir, yük taşırlar ve oral olarak uygulanmaları kısıtlıdır. Bu nedenle formülasyon için farklı yaklaşımlar geliştirilmiştir. Peptid tabanlı hidrojel sentezlenmesi ve bileşiğin hidrojele konjuge edilmesi, peptidin kumarinik asit temelli siklik bir ön ilaca dönüştürülmesi yaklaşımları stabil olmayan opioid peptidleri enzimatik parçalanmadan korur. Peptidin bir nanopartiküle yüklenmesi ve lipozomal nanotaşıyıcıların kullanılmasında nanoteknolojiden yararlanılmıştır. Multiveziküler lipozomlar (DepoFoam) kullanılarak cerrahi sonrası ağrı yönetiminde peptid temelli ilaç uygulanması mümkündür. Opioid peptidler, tedavide faydalanılabilecek birçok endikasyona sahiptir. Peptidlerin formülasyonunda çok çeşitli teknolojiler kullanılmaktadır ve bu çalışmalardan umut verici sonuçlar elde edilmiştir.

Opioid Peptides: Pharmaceutical Significance and Formulation Approaches

Opioids have been used in pain management for thousands of years due to the pain relief effects that they show by binding to their own receptors. Nowadays, their use continues in a more controlled manner because they have various side effects and a potential for dependence. Researchers have found substances that are naturally synthesized and cause opioid-like effects in the human body. These substances are known as endogenous opioid peptides. Synthetic analogs of these peptides are also synthesized. These compounds are hydrophilic due to their structure, they are charged molecules and their oral administration is limited. There are several approaches to the formulation of opioid peptides. Synthesis of peptide-based hydrogels and conjugation of the compound to a hydrogel, conversion of the peptide into a coumarinic acid-based cyclic prodrug are some of the approaches that protect unstable opioid peptides from enzyme degradation. Nanotechnology has also been used to encapsulate peptides in nanocarriers such as; nanoparticles and liposomes. In this context, research shows that it is possible to administer peptide-based drugs in post-surgical pain management using multivesicular liposomes (DepoFoam). A wide variety of technologies are used in the formulation of these peptides and promising results have been obtained from these studies.

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  • Trescot A, Datta S, Lee M, Hansen H. Opioid Pharmacology. Pain Physician. 2008; 11: 133-153.
  • Pathan H, Williams J. Basic opioid pharmacology: an update. Br J Pain. 2012; 6(1): 11-16.
  • Schwarzer C. 30 Years of Dynorphins – New Insights on Their Functions in Neuropsychiatric Diseases. Pharmacol Ther. 2009; 123(3): 353-370.
  • Goldstein A, Tachibana S, Lowney LI, Hunkapiller M, Hood L. Dynorphin-(1-13), an extraordinarily potent opioid peptide. Proc. Natl. Acad. Sci. USA. 1979; 76(12): 6666-6670.
  • Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Morgan BA, Morris HR. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature. 1975; 258(5536):577-580.
  • Li Y, Lefever M, Muthu D, Bidlack J, Bilsky E, Polt R. Opioid glycopeptide analgesics derived from endogenous enkephalins and endorphins. Future Med Chem. 2012; 4(2): 205-226.
  • Feng Y, He X, Yang Y, Chao D, Lazarus L, Xia Y. Current Research on Opioid Receptor Function. Curr Drug Targets. 2013; 13(2): 230-246.
  • Mansour A, Khachaturian H, Lewis ME, Akil H, Watson SJ. Autoradiographic differentiation of mu, delta, and kappa opioid receptors in the rat forebrain and midbrain. J Neurosci. 1987; 7(8): 2445-64.
  • Dhawan BN, Cesselin F, Raghubir R, Reisine T, Bradley PB, Portoghese PS ve ark. International Union of Pharmacology. XII. Classification of opioid receptors. Pharmacol Rev. 1996; 48 (4): 567-92.
  • Reinscheid RK, Nothacker HP, Bourson A, Ardati A, Henningsen RA, Bunzow JR. Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor. Science. 1995; 270 (5237): 792-4.
  • Lemos Duarte M, Devi L. A. Post-translational Modifications of Opioid Receptors. Trends in Neuroscience. 2020; 43 (6): 417-432.
  • Pan Z, Hirakawa N, Fields HL. A cellular mechanism for the bidirectional pain-modulating actions of orphanin FQ/nociceptin. Neuron. 2000; 26: 515–522.
  • McDonald J, Lambert DG. Opioid receptors. Contin Educ Anaesth Crit Care Pain. 2005; 5: 22–25.
  • Sobczak, M., Sałaga, M., Storr, M.A. ve ark. Physiology, signaling, and pharmacology of opioid receptors and their ligands in the gastrointestinal tract: current concepts and future perspectives. J Gastroenterol. 2014; 49: 24–45.
  • Salgado S, Kaplitt MG. The Nucleus Accumbens: A Comprehensive Review. Stereotact Funct Neurosurg. 2015; 93:75–93.
  • Li CH, Chung D. Isolation and structure of an untriakontapeptide with opiate activity from camel pituitary glands. Proc Natl Acad Sci U S A. 1976; 73(4):1145-1148.
  • Danielson PB, Dores RM. Molecular evolution of the opioid/orphanin gene family. Gen Comp Endocrinol. 1999; 113:169-186.
  • Hokfelt PT, Nilsson G. Immunohistochemical analysis of peptide pathways possibly related to pain and analgesia: enkephalin and substance. Proc Natl Acad Sci USA. 1977; 74:3081-3085.
  • McLaughlin P. Proenkephalin-Derived Peptides. Chapter 182. Kastin A, editor. Handbook of Biologically Active Peptides. 2nd ed. Academic Press; 2013.
  • Snyder SH. Opiate receptors and beyond: 30 years of neural signaling research. Neuropharmacology. 2004; 47:274-285.
  • Zagon IS, Verderame MF, McLaughlin PJ. The biology of the opioid growth factor receptor (OGFr). Brain Res Rev. 2002;38: 351-376.
  • McLaughlin PJ. Regulation of DNA synthesis of myocardial and epicardial cells in developing rat heart by [Met5]-enkephalin. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 1996; 271(1): 122-129.
  • North RA, Tonini M. The mechanism of action of narcotic analgesics in the guinea-pig ileum. Br. J. Pharmac. 1977; 61: 541-549.
  • Akil H., Watson S, Young E., Lewis M., Khachaturian H., Walker JM. Endogenous Opioids: Biology and Functions. Ann. Rev. Neurosci. 1984; 7:223-55.
  • Zagon I., McLaughlin P. Endogenous opioid systems regulate growth of neural tumor cells in culture. Brain Research. 1989; 490: 14-25.
  • Henry M, Gendron L, Tremblay M, Drolet G. Enkephalins: Endogenous Analgesics with an Emerging Role in Stress Resilience. Neural Plast. 2017.
  • Mains R, Eipper B, Ling N. Common precursor to corticotropins and endorphins. Proc. Natn. Acad. Sci. U.S.A. 1977; 74(7): 3014-3018.
  • Loh H, Tseng LF, Wei E, Li CH. Beta-Endorphin is a potent analgesic agent. Proc Natl Acad Sci USA. 1976; 73(8): 2895-2898.
  • Lee M, Wardlaw SL. Beta-Endorphin. Fink G, editor. Encyclopedia of Stress. 2nd ed. Academic Press; 2007.
  • Comb M, Seeburg P, Adelman J, Eiden L, Herbert E. Primary structure of the human Met- and Leu-enkephalin precursor and its mRNA. Nature. 1982; 295: 663-666.
  • Teschemacher H, Opheim KE, Cox BM, Goldstein A. A peptide-like substance from pituitary that acts like morphine-Isolation. Life Sci. 1975; 16(12): 1771-1775.
  • Goldstein A, Fischli W, Lowney L, Hunkapiller M, Hood L. Porcine pituitary dynorphin: Complete amino acid sequence of the biologically active heptadecapeptide. Proc. Natl. Acad. Sci. USA. 1981; 78(11): 7219-7223.
  • James IF, Fischli W, Goldstein A. Opioid receptor selectivity of dynorphin gene products. J Pharmacol Exp Ther. 1984; 228(1):88-93.
  • Sharma SK, Klee WA, Nirenberg M. Opiate-dependent modulation of adenylate cyclase. Proc Natl Acad Sci U S A. 1977; 74(8):3365-3369.
  • North RA, Williams JT, Surprenant A, Christie MJ. Mu and delta receptors belong to a family of receptors that are coupled to potassium channels. Proc Natl Acad Sci U S A. 1987; 84(15):5487-5491.
  • Jin W, Lee NM, Loh HH, Thayer SA. Dual excitatory and inhibitory effects of opioids on intracellular calcium in neuroblastoma x glioma hybrid NG108-15 cells. Mol Pharmacol. 1992; 42(6):1083-1089.
  • Barg J, Belcheva MM, Rowiński J, Coscia CJ. kappa-Opioid agonist modulation of [3H]thymidine incorporation into DNA: evidence for the involvement of pertussis toxin-sensitive G protein-coupled phosphoinositide turnover. J Neurochem. 1993; 60(4):1505-1511.
  • Nikolarakis KE, Almeida OF, Yassouridis A, Herz A. Presynaptic auto- and allelo-receptor regulation of hypothalamic opioid peptide release. Neuroscience. 1989; 31(1):269-273.
  • Woods AS, Kaminski R, Oz M, Wang Y, Hauser K, Goody R ve ark. Decoy peptides that bind dynorphin noncovalently prevent NMDA receptor-mediated neurotoxicity. J Proteome Res. 2006; 5(4):1017-1023.
  • Kanemitsu Y, Hosoi M, Zhu PJ, Weight FF, Peoples RW, McLaughlin JS ve ark. Dynorphin A inhibits NMDA receptors through a pH-dependent mechanism. Mol Cell Neurosci. 2003; 24(3):525-537.
  • Shippenberg TS, Zapata A, Chefer VI. Dynorphin and the pathophysiology of drug addiction. Pharmacol Ther. 2007; 116(2):306-321.
  • Chavkin C. Dynorphin–Still an Extraordinarily Potent Opioid Peptide. Mol Pharmacol. 2013; 83(4): 729-736.
  • Zadina JE, Hackler L, Ge LJ, Kastin AJ. A potent and selective endogenous agonist for the mu-opiate receptor. Nature. 1997; 386: 499-502.
  • Gu Z, Wang B, Kou Z, Bai Y, Chen T, Dong Y ve ark. Endomorphins: Promising Endogenous Opioid Peptides for the Development of Novel Analgesics. Neurosignals. 2017; 25:98-116.
  • Zadina JE, Gerall AA, Kastin AJ, Hackler L, Ge LJ, Zhang X ve ark. Endomorphins: novel endogenous mu-opiate receptor agonists in regions of high mu-opiate receptor density. Ann N Y Acad Sci. 1999; 897: 136-144.
  • Zadina JE, Nilges MR, Morgenweck J, Zhang X, Hackler L, Fasold MB. Endomorphin analog analgesics with reduced abuse liability, respiratory depression, motor impairment, tolerance, and glial activation relative to morphine. Neuropharmacology 2016; 105: 215-227.
  • Zupancic O, Rohrer J, Lam H, Griebinger JA. Development and in vitro characterization of self-emulsifying drug delivery system (SEDDS) for oral opioid peptide delivery. Drug Development and Industrial Pharmacy. 2017; 43: 1694-1702.
  • Lalatsa A, Lee V, Malkinson J, Zloh M, Schatzlein A, Uchegbu I. A Prodrug Nanoparticle Approach for the Oral Delivery of a Hydrophilic Peptide, Leucine5-enkephalin, to the Brain. Molecular Pharmaceutics. 2012; 9: 1665−1680.
  • Karls, MS, Rush, BD, Wilkinson, KF, Vidmar, TJ, Burton, PS, Ruwart, MJ. Desolvation Energy a Major Determinant of Absorption, but Not Clearance, of Peptides in Rats. Pharm. Res. 1991; 8(12): 1477−1481.
  • Egleton R, Mitchell S, Huber J, Polt R. Improved blood-brain barrier penetration and enhanced analgesia of an opioid peptide by glycosylation. Journal of Pharmacology and Experimental Therapeutics. 2001; 299(3): 967-972.
  • Brownson EA, Abbruscato TJ, Gillespie TJ, Hruby V, Davis T. Effect of peptidases at the blood brain barrier on the permeability of enkephalin. Journal of Pharmacology and Experimental Therapeutics. 1994; 270(2): 675-680.
  • Shen WC. Oral peptide and protein delivery: Unfulfilled promises?. DDT. 2003; 8(14): 607-608.
  • Martin C, Mannes M, Lantero A, Bucher D, Walker K, Wanseele Y ve ark. Biodegradable Amphipathic Peptide Hydrogels as Extended-Release System for Opioid Peptides. J. Med. Chem. 2018; 61: 9784-9789.
  • Dasgupta, A., Mondal, J. H., Das, D. Peptide hydrogels. RSC Adv. 2013; 3 9117−9149.
  • [Leu]Enkephalin. [10 Kasım 2021]. Erişim adresi: https://pubchem.ncbi.nlm.nih.gov/compound/Leu_enkephalin
  • Siew A, Le H, Thiovolet M, Gellert P, Schatzlein A, Uchegbu I. Enhanced Oral Absorption of Hydrophobic and Hydrophilic Drugs Using Quaternary Ammonium Palmitoyl Glycol Chitosan Nanoparticles. Mol. Pharmaceutics. 2012; 9 (1): 14−28.
  • Cheng WP, Gray AI, Tetley L, Hang TLB, Schatzlein AG, Uchegbu IF. Polyelectrolyte nanoparticles with high drug loading enhance the oral uptake of hydrophobic compounds. Biomacromolecules. 2006; 7 (5): 1509−1520.
  • Uchegbu I.F., Lane, M., Schatzlein, A. G. Nanomedicines from polymeric amphiphiles. Torchilin V., AmijiIn M., editor. Handbook of Materials for Nanomedicine. 1st ed. Stanford Publishing, 2013.
  • Lindqvist A. Quantitative Aspects of Nanodelivery Across the BloodBrain Barrier Exemplified with the Opioid Peptide DAMGO [PhD thesis]. Sweeden: Uppsala University; 2016.
  • Gudmundsson OS, Pauletti GM, Wang W, Shan D, Zhang H, Wang B ve ark. Coumarinic Acid-Based Cyclic Prodrugs of Opioid Peptides that Exhibit Metabolic Stability to Peptidases and Excellent Cellular Permeability. Pharmaceutical Research. 1999; 16(1).
  • Kiptoo P, Laksitorini M, Siahaan T. Blood-Brain Peptides: Peptide Delivery. Chapter 233. Kastin A., editor. Handbook of Biologically Active Peptides. 2nd ed. Academic Press, 2013.
  • Ye Q, Asherman J, Stevenson M, Brownson E, Katre N. DepoFoam™ technology: a vehicle for controlled delivery of protein and peptide drugs. Journal of Controlled Release. 2000; 64(1-3): 155-166.

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APA Engin, D. , Timur, S. S. , Muçaj, S. & Gürsoy, R. N. (2023). Opioid Peptidleri: Farmasötik Açıdan Önemi ve Formülasyon Yaklaşımları . Hacettepe University Journal of the Faculty of Pharmacy , 43 (3) , 243-260 . DOI: 10.52794/hujpharm.1109147
Hacettepe Üniversitesi Eczacılık Fakültesi Dergisi
  • Yayın Aralığı: Yılda Yılda 4 Sayı
  • Yayıncı: Hacettepe Üniversitesi

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