Current Topics in Medicinal Chemistry - Volume 4, Issue 1, 2004

I wish to take this opportunity at the start of the fourth year of publication for Current Topics in Medicinal Chemistry (CTMC) to consider where the journal has come and is heading in the future. This issue (vol 4 / 1) marks the 33rd since publication began in 2001. There were six issues that year, 12 in 2002, and 14 in 2003. We will have 16 issues in 2004 and, remarkably, many of these have already been received and are in the galley proof stage. Although Bentham must commit as to the number of issues for a particular year in advance, and each issue has ca. 90-120 pages, CTMC has flexibility as to when the issues appear. Since we have a considerable number of issues in hand and ready to print, we will be publishing three in both January and February. I am pleased to report that the journal has published a series of excellent issues containing quality manuscripts, and I thank all of the Guest Editors for their contributions. The topics covered have been broadly spaced in the general areas of medicinal chemistry, bioorganic chemistry, and new technologies. Prominent and popular issues have involved the thematic coverage of a particular protein target or a more general and inclusive review of a disease or therapeutic area. The scientific journal as we know it will rely in the future even more heavily upon online publication and abstracting for distribution. CTMC is covered by all of the major scientific abstracting services, and individual abstracts for the articles can be found online at the journal website (http: / / www.bentham.org / ctmc / ). Manuscripts can be ordered separately and directly from this website via Ingenta. Electronic as well as print subscriptions are available. As a sign of things to come, an annual book series from Bentham entitled “Frontiers in Medicinal Chemistry” will initiate publication solely online in January. However, even in this age of an almost overwhelming access to information, or perhaps because of that, there is a place for the hardcopy publication of secondary scientific review journals such as CTMC. By holding the journal and opening the cover, one can peruse research summaries and approaches to information that cannot be easily found elsewhere. I wish to thank Bentham Science Publishers and Dr. Matthew Honan for support. I also appreciate the willingness of so many distinguished scientists to be on the Editorial Advisory Board. Ambreen Wasim, Mahmood Alam, and their associates at the Bentham office in Pakistan manage the production of the journal, and I thank Barbara Calhoun, my Editorial Assistant here at Spring House, for her conscientious efforts.

Opioids were among the earliest neuropeptides identified in the nervous system. They are some of the most effective pain-relieving drugs used in the clinical management of pain. In addition to their analgesic effect, opioid peptides also affect a number of physiological functions, including hormone secretion, neurotransmitter release, feeding, gastrointestinal motility, and respiratory activity. Research on opioids has been carried out for about 30 years. An enormous amount of experimental material has been accumulated. The recent identification of multiple opioid receptors, as well as the development of peptide agonist and antagonist analogs for each of these receptors has provided a framework to explore functional roles of opioids. The present issue, containing five articles, provides a brief overview on only a few aspects of opioid chemistry and physiology. The authors review the main developments that have led to potent and selective peptide analogs at three main receptors, their bioavailability and resistance against enzymatic degradation. They survey the relationship of opioid peptides to such undesirable side-effects as addiction and tolerance and discuss some biological functions of opioids, including their role in inflammatory responses and gastric function (in this case the role of other neuropeptides, not only opioids is discussed). I would like to thank the authors of this issue for their valuable contributions.

This review gives a historical perspective, summarizing approximately 25 years of research on opioids. The “typical” opioid peptides produced in the brain, “atypical” opioids encrypted in milk protein or hemoglobin sequences, and extremely potent and selective opioids of amphibian origin are described. The main focus is on the structure-activity relationship studies of peptide ligands for three main opioid receptor types (μ, δ, κ), their selectivities and pharmacological activities in vitro. Chemical modifications that led to obtaining potent and selective agonists and antagonists for these receptors are discussed.

The search for new peptides to be used as analgesics in place of morphine has been mainly directed to develop peptide analogues or peptidomimetics having higher biological stability and receptor selectivity. Indeed, most of the alkaloid opioid counterindications are due to the scarce stability and the contemporary activation of different receptor types. However, the development of several extremely stable and selective peptide ligands for the different opioid receptors, and the recent discovery of the μ-receptor selective endomorphins, rendered this search less fundamental. In recent years, other opioid peptide properties have been investigated in the search for new pharmacological tools. The utility of a drug depends on its ability to reach appropriate receptors at the target tissue and to remain metabolically stable in order to produce the desired effect. This review deals with the recent investigations on peptide bioavailability, in particular barrier penetration and resistance against enzymatic degradation; with the development of peptides having activity at different receptors; with chimeric peptides, with propeptides, and with non-conventional peptides, lacking basic pharmacophoric features.

There is significant experimental evidence implicating the endogenous opioid system (opioid peptides and opioid receptors) with the processes of reward and reinforcement. Indeed, many behaviors associated with reward and reinforcement, for example feeding behavior, are controlled by distinct components of the endogenous opioid system located in relevant brain regions. It has also been shown that regardless of their initial site of action many drugs of abuse, such as morphine, nicotine, cocaine, alcohol and amphetamines, induce an increase in the extracellular concentration of dopamine in the nucleus accumbens. This increased secretion of dopamine in the nucleus accumbens seems to be a common effect of many drugs of abuse, and it was proposed that may mediate their rewarding and reinforcing properties. Furthermore, activation of μ opioid receptors in the ventral tegmental area, or of μ and δ opioid receptors in the nucleus accumbens enhances the extracellular concentration of dopamine in the nucleus accumbens. Thus, stimulation of the activity of distinct components of the endogenous opioid system either by opioid or by other drugs of abuse, may mediate some of their reinforcing effects. In this review article, a brief description of the endogenous opioid system and its implication in the processes of reward and reinforcement of opioid and other drugs of abuse will be presented. Furthermore, the use of opioid antagonists in the treatment of drug addiction will be discussed. Special emphasis will be given to ethanol addiction, the drug mainly studied in my laboratory.

Opioid receptors (OR) and their mRN A are present in the central and peripheral nervous system of mammals. In this review we examine the behavioral effects of opioids and the expression of their receptors during peripheral inflammation in two experimental models: the rat paw and the mouse intestine. Inflammation increased the antinocice ptive (paw) and the inhibitory effects of opioids in the gut (transit, permeability and plasma extravasation) by interaction with OR located at peripheral sites. Based on agonist efficacy, μ > δ >> κ-OR media te the a ntinociceptive and a ntitr ansit e ffe cts of opioids during inflammation. Intestinal pe rmeability is modula te d by δ = μ >> κ-O R, while κ > δ >> μ-O R are involved in the inhibition of plasma extravasation. Intestinal inflammation increased the transcription of μ and δ-OR (but not κ) genes in the gut, thus explaining the enhanced antitransit and antisecretory effects of m and δ-OR agonists; however, the increased inhibitory effects of κ-OR agonists on plasma extravasation could result froμ post-transcriptional regulation of the receptor. Similarly, the increased expression of peripheral m-OR observed in the rat paw during inflammation, occurs at post-transcriptional levels and is related to an increased axonal transport from the dorsal root ganglia to peripheral terminals. The sites and mechanisms implicated in the increased transcription of μ and δ-OR during intestinal inflammation are under investigation.

The role of central nervous system (CNS) in regulation of gastric function has long been known. The dorsal vagal complex (DVC) has an important role in regulation of gastric mucosal integrity; it is involved both in mucosal protection and in ulcer formation. Neuropeptides have been identified in DVC, the origin of these peptides are both intrinsic and extrinsic. Neuropeptides are localized also in the periphery, in afferent neurons. The afferent neurons also have efferent-like function in the gastroinetestinal tract, and neuropeptides released from the peripheral nerve endings of primary afferent neurons can induce gastric mucosal protection. Centrally and / or peripherally injected neuropeptides, such as amylin, adrenomedullin, bombesin, cholecystokinin, neurotensin, opioid peptides, thyreotropin releasing hormone and vasoactive intestinal peptide, influence both the acid secretion and the gastric mucosal lesions induced by different ulcerogens. The centrally induced gastroprotective effect of neuropeptides may be partly due to a vagal dependent increase of gastric mucosal resistance to injury; activation of vagal cholinergic pathway is resulted in stimulation of the release of mucosal prostaglandin and nitric oxide. Furthermore, release of sensory neuropeptides (calcitonin gene-related peptide, tachykinins) from capsaicin sensitive afferent fibers are also involved in the centrally induced gastroprotective effect of neuropeptides.

Extensive efforts since 1931, on the structural determination of the mammalian tachykinin SP by NMR, CD and IR have turned out to be inconclusive. Studies are now being concentrated on the structural properties and characteristics of various NK receptors (NK1, NK2 and NK3) with the help of genetics, cloning, receptor engineering, mutagenesis and modeling. This knowledge is now being fruitfully used in the development of non-peptide NK1 receptor antagonists that essentially block the pharmacological effects of SP. It is now being realized that the simultaneous blockade of two or more receptors gives promising results in emesis, depression and pulmonary obstructive diseases. In addition to the synthetic compounds, the discovery of antagonists from natural origin has added a great value to this field. In this review we have made an attempt to present the structural characteristics of SP, its analogs and antagonists, the structural characteristics of the NK receptor, and structure activity relationships that have helped to improve the therapeutic utilities of SP antagonists.

Despite of the recent advances in the structural investigation of complex molecules, the comprehension of the 3D features responsible for the interaction between opioid peptides and μ- opioid receptors still remains an elusive task. This has to be attributed to the intrinsic nature of opioid peptides, which can assume a number of different conformations of similar energy, and to the flexibility of the receptorial cavity, which can modify its inner shape to host different ligands. Due to this inherent mobility of the ligand-receptor system, massive efforts devoted to the definition of a rigid bioactive conformation to be used as a template for the design of new pharmacologically active compounds might be overstressed. The future goal might be the design of peptide or nonpeptide ligands capable of maximizing specific hydrophobic interactions. This review covers the recent opinions emerged on the nature of the ligand-receptor interaction, and the development of suitable models for the determination of the bioactive conformation of peptide ligands active towards m-opioid receptors.

In this review the conformational studies of natural enkephalins (H-Tyr-Gly-Gly-Phe- Met-OH the [Met5]enkephalin and H-Tyr-Gly-Gly-Phe-Leu-OH; the [Leu5]enkephalin), their acyclic and cyclic analogues, including those carried out in our laboratory, performed by experimental and theoretical methods and their combination, are described. Emphasis is given on the role of conformational constraints introduced by cyclization on activity at the μ and δ opioid receptors. Comparison of the conformations of cyclic enkephalin analogues with high δ-receptor activity with those of potent rigid non-peptide δ-receptor agonists indicates that the proximity of the aromatic side chains in positions 1 and 4 as well as the N-terminal amino group is desirable for the activity at the d opioid receptors; early conformational studies also suggested that spatial separation of the aromatic side chains and rigidity of the cyclic backbone is desirable for μ-receptor activity. The results of our recent conformational studies performed with the use of fluorescence and NMR spectroscopy as well as theoretical calculations indicate, however, that these structural features are not necessary for activity at the m opioid receptors. Methods applied to the determination of the conformation of flexible peptides, such as Nuclear Magnetic Resonance (NMR), fluorescence spectroscopy, and theoretical conformational analysis are also discussed briefly.

Determination of conformations and structures of opioid peptides in the membrane environments is an essential step to understand the action of the peptide to the specialized receptors. This information not only gains insight into the structure-function relationship of opioid peptide but also gives proper guidelines to design a new drug to have same neuroendocrine functions. This review provides the structural studies of three types of opioid peptide families such as enkephalin, β-endorphin and dynorphin in the solid states and the membrane environments. The structures of enkephalins show that they take β-bend, extended and double β-bend structures in the crystals. Moreover, enkephalin molecules take a variety of structures in the crystals and are easily converted to the other structures with slightly different torsion angles. On the other hand, β-bend structures are mostly seen in the membrane environments. Membrane bound structure of dynorphin shows that the N-terminus forms α-helixal structure and is inserted into the membrane with the helical axis almost perpendicular to the membrane surface. It is discussed that the helical region of the extracellular loop II of the κ- opioid receptor may interact with the helical region of dynorphin with a high affinity in the membrane environments. β- endorphin takes α-helical structure at N-terminus and the central regions and the rest of regions take unordered structure when they bind to the membrane. Since the membrane bound structures of opioid peptides differ from those of the solution states, membrane association is an important process for exerting the affinity and the selectivity to the specific opioid receptors.

The availability of new, highly selective antagonists, in the field of opioid peptides and of other pain peptides, is important both for a better understanding of the interaction of the receptors with their ligands and for their practical relevance. The design of antagonists is not obvious even when the essential features of agonists are well known. In this review we have examined the main aspects of the problem using, as leading criteria two theoretical models of antagonism and the subdivision of opioid peptides into two functional domains. The main causes of antagonism have been integrated in two very general models: one, referred to as the participation model, attributes antagonism to the lack, with respect to the parent agonist, of an essential group, whereas another model, attributes antagonism to the misfit of the molecule inside the receptor. The second criterion is the division of the structure of peptide hormones, originally put forward by Robert Schwyzer, in two functional domains, the message domain, which is responsible of the larger part of the binding affinity of opioid agonists, and an address domain, which dictates most of the peptide specificity. The most significant achievements in the design of opioid antagonists are classified according to the relative importance of chemical constitution, conformation and chirality.

Darvas, F.; Keseru, G.; Papp, A.; Dorman, G.; Urge, L.; Krajcsi, P. Curr. Top. Med. Chem. 2002, 2, 1287-1304. In this manuscript, several paragraphs were directly copied from an earlier publication written by a different author without proper attribution (Clark, D. E. Combinatorial Chemistry and High Throughput Screening 2001, 4, 477-496). Specifically, the lead paragraph under “General Concepts in Absorption” on page 1288 and the lead paragraph on page 1289 under “Polar Surface Area” were taken verbatim without reference to their source. It would have been more appropriate to have included these paragraphs in quotations and cited the appropriate reference.