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Natural Opioid Peptides, Synthetic Analogs, Peptidases: Pharmacological Analysis and Drug Design

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Natural Opioid Peptides, Synthetic Analogs, Peptidases: Pharmacological Analysis and Drug Design SEMMELWEIS UNIVERSITY Doctoral School of Pharmaceutical and Pharmacological Sciences NATURAL OPIOID PEPTIDES, SYNTHETIC ANALOGS, PEPTIDASES: PHARMACOLOGICAL ANALYSIS AND DRUG DESIGN by András Z. Rónai Ph.D. Dissertation Supervisor: Prof. Dr. Kálmán Magyar, D.Sc. Member of Hungarian Academy of Sciences Department of Pharmacology and Pharmacotherapy Semmelweis University, Budapest Budapest, 2004 1 To Sándor Bajusz 2 CONTENTS 1. Introduction 2. List of abbreviations 3. Results and Conclusions 3.1. Chapter 1. Critical overview of the use of isolated organs in opioid research 3.2. Chapter 2. Pharmacological characterisation of enkephalins, b-endorphin and its fragments 3.3. Chapter 3. Development of potent analgesic enkephalin analogs such as (D-Met2,Pro5) -enkephalinamide 3.4. Chapter 4. Characterisation of structural principles for the receptor type-selectivity of enkephalin analogs 3.5. Chapter 5. Detection of a novel dipeptidyl-carboxypeptidase in rodent blood vessel and human adrenomedullary tumors 3.6. Chapter 6. Design and pharmacological characterisation of novel, pure and highly d -opioid receptor type-selective and k-opioid receptor type.selective peptide antagonists: the principle of N-acylation. 3.7. Chapter 7. Present and future: endomorphins, nociceptin. 4. General summary and conclusions 5. Acknowledgement 6. References 7. Patents 8. Appendix. 3 1. Introduction The cornerstone of opioid peptide history was the discovery of enkephalins (Tyr-Gly-Gly- Phe-Met, (Met5) enkephalin and Tyr-Gly-Gly-Phe-Leu, (Leu5)-enkephalin) in porcine brain by Hughes, Kosterlitz and their coworkers in 1975 (53). The history appeared to obey the principle of receptor theory declaring that a receptor should have one or more endogenous ligand(s). The first opioid receptor model has been set forth by Beckett and Casy (11). The direct evidence for the existence of opioid receptors (i.e. the accomplishment of receptor binding assay) has been supplied simultaneously and independently by three teams (97, 142, 151). Soon after the the discovery of enkephalins the heterogeneity of opioid receptors, i.e. the existence of multiple receptor types has also been proved and the main pharmacological properties of receptor types (m, k and d as major ones and also, tentatively, s) have also been documented (33, 77, 81). Since the (Met5)-enkephalin sequence is present in a pituitary hormone, b-lipotropin (LPH(1-91), b-LPH), between sequence positions 61-65, the attention has been focussed on this peptide hormone. b-LPH is the biological source of several natural opioid sequences, each bearing the Tyr-Gly-Gly-Phe-Met motif at the N-terminus (a-, b- and g-endorphins) but not of enkephalins. Of these active sequences, the untriakontapeptide b-endorphin (LPH(61- 91), b-EP) is the most important (15, 44, 76). A third distinct opioid peptide family, based on the N-terminal Tyr-Gly-Gly-Phe-Leu motif, the dynorphin-neo-endorpin group has also been recognized by the late seventies (35, 57). The large molecular-weight precursors of these three opioid peptide families, pre-proopio- melanocortin for endorphins, pre-proenkephalin for enkephalin-related peptides and pre- prodynorphin have duly been identified in the early eighties (23, 56, 87). In the same period (late seventies-early eighties) two entirely novel natural opioid peptide groups have been recognized. One is referred to as the family of Tyr-Pro-peptides; in this group remarkable opioid agonist activity was present if the N-terminal dipeptide motif was followed by aromatic amino acid. Casomorphin-related peptides, hemorphins and cytochrophins fell strictly into this family (16-18) with a-gliadorphin (37) and Tyr-MIF-1/Tyr-W-MIF-1 (26, 59) at the "outskirts" of assembly. The other group, under the heading of "amphibian skin opioid peptides", was heralded by the discovery of dermorphin (27); The characteristic N- terminal motif in this peptide (and the ones to follow) was Tyr-D-Ala/D-Met-Phe--. The former family was "crowned" by the discovery of endomorphins in 1997 (158) whereas the latter gave rise to dermenkephalin and deltorphins (28). The primary structures of all the three 4 major types (i.e. d, m and k) of opioid receptor proteins were deduced between 1992 and 1994 (29, 62; for review see 155). This discovery gave further impetus to the analyses directed at ligand binding, receptor heterogeneity and signal transduction (e.g. 100, 159). My experiments were carried out in two periods, between 1976 and 1984 and 1988 and 2001, with a distinct and painful "silent gap" between 1984 and 1988. There was a chrononological overlap between some of the thematically distinct projects but, occasionally, several issues were re-instated after a dormant period of 8-10 years. Between 1976 and 1981, the work was done at the Institute of Drug Research, in cooperation with preparative biochemists (Groupleader L. Gráf) , peptide synthetic chemists (Groupleader S. Bajusz) and behavioral pharmacologists (Groupleader J.I. Székely). My first task, being the Groupleader of "In vitro pharmacological unit" was to characterize the pharmacological properties of (Met5)-enkephalin, b-endorphin and its fragments (Chapter 1). This entailed of finding a proper assembly of isolated organs and experimental paradigms suitable for differentiating pharmacologically between morphine-like non-peptidic substances and opioid peptides and also between opioid peptides themselves (Chapter 2). The next tasks were to give logistic support to the design of analgesic enkephalin analogs (Chapter 3), to characterize the structural principles in enkephalin analogs responsible for receptor type selection and to find the "thumb rules" of correlating in vitro pharmacological properties with analgesia (Chapter 4). Among the potential factors affecting the in vivo effectiveness of enkephalin analogs, one had to consider their increased stability against biodegradation. Natural enkephalins and some other pro-enkephalin derived natural peptides are rapidly destroyed by various peptidases. While studying these aspects, I became aware of a novel peptidase activity in some rodent and human tissues (Chapter 5); these pursuits took place between 1981-1983 and 1990- 1997,.respectively. It is a perpetual challange in receptor chemistry/pharmacology to design competitive, receptor type/subtype-selective antagonist when the structure and pharmacological profile of natural and synthetic agonist ligand sets are known (Chapter 6). This chapter is an etude of pharmacologist with the additional curiosity that, by lacking a better candidate for the task, the drug design had to be done by myself in the case of d-opioid receptor antagonist peptide analogs and, in part, also in the case of k-opioid receptor antagonist peptides. To relate drug structure to pharmacological activities the knowledge of conformational properties is an important issue. In the case of b-LPH-related peptides the conformational analyses were organised by the biochemist (39, 40), in the case of (D- Met2,Pro5)-enkephalinamide by the synthetic chemist (49) whereas for some other sets of 5 analogs I made the structured proposal for the conformational analysis/modelling (50, 113, 145). Each project gave a conclusive and well-defined result but never the achievement to my real satisfaction. I consider them as "truncated" projects mostly because the lack of proper funding; several sprouts are still open to further cultivation. In this context, I wish to quote the proverbial sentence attributed to Professor W.D.M. Paton: "My task is to invent an original idea and prove that it is worthy of attention. All the other details may be done by others". 2. List of abbreviations Note: all abbreviations are written out in full when they are first mentioned in the text For specifying primary structures of peptedes, either the three-letter or the single-letter conventional amino acid codes are used. Ac= acetyl ACE= angiotensin-converting enzyme, EC 3.4.15.1 All= allyl ART= isolated, perfused rabbit ear artery AT-I=angiotensin-I AT-II= angiotensin-II ß-EP= b-endorphin, porcine, b-lipotropin-(61-91) (unless otherwise indicated, purified from porcine pituitary extract BK= bradykinin BOC or t-BOC= tertiary butoxycarbonyl CD= circular dichroism CNM= isolated, field-stimulated cat nictitating membrane (medial part) CNS= central nervous system DADLE= (D-Ala2,D-Leu5)-enkephalin DAMGO= (D-Ala2,MePhe4,Gly5-ol)-enkephalin DPDP= (D-Pen2,D-Pen5)-enkephalin EDTA= ethylenediamine-tetraacetic acid EKC= ±ethylketocyclazocine For= formyl FT-IR= Fourier-transform infrared GPI= isolated longitudinal muscle strip-Auerbach plexus of guinea-pig ileum 6 HFR= hippuryl-phenylalanyl-arginine HHL= hippuryl-histidyl-leucine HRF= hippuryl-argynyl-phenylalanine HYR= hippuryl-tyrosyl-arginine IC50= 50% inhibitory concentration icv= intracerbroventricular (third ventricle, lateral horn) injection Ke= equilibrium dissociation constant LPH= b-lipotropin-(1-91), porcine (unless otherwise indicated, purified from porcine pituitary extract) LVD= rabbit vas deferens ME= (Met5)-enkephalin ME-RF= (Met5)-enkephalin-Arg6,Phe7 MVD= isolated mouse vas deferens NEP= neutral endopeptidase, EC 3.4.24.11 PD-117 302=(±)-trans-N-methyl-N,N-[2-(l-pyrrolidinyl)-cyclohexyl]benzo[b]thiophene-4 -acetamide monohydrochloride Piv= pivaloyl POMC= pro-opiomelanocortin Prop= propionyl RVD= isolated rat vas deferens t-Bu= tertiary butyl TIPP= Tyr-Tic-Phe-Phe 3.Results and Conclusions 3.1. Chapter 1. Critical overview of the use of isolated organs in opioid research The isolated organs
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