The Delta Receptor PDF

Preface

The discovery of a receptor selective for opioids in 1973 heralded a heightened interest in opioid research into mechanisms of endogenous control of pain and in efforts to develop new analgesics. The initial simultaneous discovery of the opiate receptor by Candace Pert, Solomon Snyder, Lars Terenius, and Eric Simon rapidly led to a search for the identification and characterization of endogenous ligands for the opiate receptor and revealed the existence of a long-suspected endogenous system of pain regulation. In rapid succession, Hans Kosterlitz, John Hughes, and their colleagues discovered the enkephalins, C. H. Li discovered the endorphins, and Avram Goldstein identified the dynorphins. Interest in opiate research and mechanisms had never been higher.

Strong pharmacological data had indicated that the properties of opiate agonists could not be satisfactorily described based on evidence of a single opioid receptor. W. R. William Martin described significantly differing behavioral properties of opiates in the chronic spinal dog and postulated the existence of three distinct opiate receptors, which he termed mu, kappa, and sigma. Between 1977 and 1979, J. A H. Lord, Hans Kosterlitz, and their colleagues demonstrated differential activity profiles of [Leu5]enkephalin, [Met5] enkephalin, and morphine in isolated tissue assays. Using the mouse isolated vas deferens and the guinea pig isolated ileum preparations they proposed the existence of a receptor preferentially expressed in the mouse vas deferens that they termed the ‘‘delta'' (for vas deferens) opioid receptor. Many subsequent radioreceptor binding and autoradiographic localization studies in vitro confirmed the existence of this receptor that was not preferential for morphine, now believed to act at a receptor termed the mu receptor by Martin and colleagues. The identification of a receptor for the endogenous enkephalins led to investigations of the physiological and pharmacological properties of these endogenous ligands and of the delta receptor itself. Understanding these issues is a journey that has been in progress for some 30 years.

Understanding the physiology and pharmacology of the delta receptor was limited initially by a lack of ligands suitable for in vivo studies. Although [Leu5]enkephalin or [Met5]enkephalin acted preferentially at the delta receptor, the selectivity of these straight-chain pentapeptides for the delta receptor over other opioid receptors was quickly found to be quite low. Additionally, and perhaps more importantly, these peptides lacked sufficient stability to be useful as a tool for the in vivo characterization of the properties mediated by activation of the delta receptor. Attempts to overcome these issues began with the inclusion of the D-enantiomer of constituent amino acids of the pentapeptide which produced less labile enkephalin derivatives, such as [D-Ala2, DLeu 5]enkephalin (DADLE) or Tyr-D-Ser-Gly-Phe-Leu-Thr (DSLET), making it possible for certain behavioral studies to be performed. However, these substances were still considerably labile in vivo. In the early 1980s, Victor Hruby, Henry Mosberg, and their associates developed the novel concept of introducing conformational constraints and discovered a class of cyclic penicillamine derivatives of enkephalin, which include [D-Pen², D-Pen5]enkephalin (DPDPE), and [D-Pen2, L-Pen5]enkephalin (DPLPE). These peptides were important in that they increased selectivity for the delta receptor significantly and additionally gained a great deal of stability in vivo, allowing their use for in vivo studies.

This development was soon followed by the discovery of the deltorphins, peptides derived from the skin of the frog Phyllomedusa sauvagei by Vittorio Erspamer, Lucia Negri, and colleagues. The deltorphins showed superb selectivity for the delta receptor and became an important tool for in vivo characterization. A potentially significant consequence of the availability of these stable, selective delta receptor agonists was the pharmacological identification of two subtypes of the delta receptor. Also critical in the investigation of the receptor and its physiology was identification of peptidic ligands which showed high selectivity for the receptor but acted as antagonists. Here, Peter Schiller and his colleagues developed TIPP and TIPPpsi as ligands, which proved enormously important in the characterization of the receptor.

An important limitation of peptidic ligands is that of systemic bioavailability. Most of the data collected with the peptidic ligands described above came from direct injections into the brain or spinal cerebrospinal fluid or through in vitro studies of receptor function. In order to circumvent the problems inherent with peptides, the development of nonpeptidic agonists had to be undertaken. Kwen-Jen Chang and Robert McNutt reported a breakthrough in identification of a nonpeptidic structure with significant selectivity for the delta agonist. This compound,BW373U86, was shown to be a systemically active, delta antinociceptive agent and led to further important studies, which led to the identification of even more selective molecules. Silvia Calderon and Kenner Rice developed a series of compounds based on the structure of BW373U86. The chiral methylether derivative SNC-80 showed greater selectivity for the delta opioid receptor, but was apparently associated with a brief single episode of convulsant activity, seeming to indicate potential limitations in the therapeutic value of delta receptor agonists. Structurally similar compounds that did not bind to the delta receptor were also shown to produce similar convulsant activity, confusing the issue of whether convulsant activity was an effect associated with the delta receptor itself, or with the specific structure.

Studies in animals and primates with these highly selective delta agonists begin to reveal that unlike mu opioid agonists such as morphine, oxycontin, fentanyl, etc., agents acting at the delta receptor are unlikely to produce addictive liability and respiratory depression. In fact, delta agonists may actually counteract those side effects induced by mu opioids.

As important as the development of highly selective agonists for the delta receptor was the identification of selective nonpeptidic antagonists for the receptor.Working together, Aki Takemori and Phil Portoghese produced a series of molecules that have been used to define the receptor. Naltrindole, a selective, nonpeptidic and systemically available delta antagonist, became widely used to characterize the function of the receptor in vivo, and its radiolabeling led to many important studies characterizing the distribution and role of the receptor.

Perhaps the most important breakthrough of delta receptor biology came with the first cloning of the opioid receptor. Chris Evans and Brigitte Kieffer simultaneously reported the cloning of the delta receptor, the first one to be cloned, and this led to the confirmation of the existence of receptor in mouse and rat tissues. Henry Yamamura and his colleagues ultimately reported the identification of the human delta receptor. These studies also led to the important identification of distribution of the receptor in the nervous system initially through autoradiography and later through the elegant development of antibodies for the receptor by Robert Elde and Tomas Hokfelt. These, and other, investigators have extensively characterized the receptor in primary afferent fibers, in the spinal dorsal horn, and in the brain. Others confirmed the existence of the delta receptor in the submucous plexus of the gastrointestinal tract.

The understanding of the molecular and cellular signal transduction mechanism is well advanced for the delta receptor. The delta receptor belongs to the superfamily of the G-protein-coupled receptors (GPCR). Through the coupling of various G-proteins, the activation of the delta receptor can lead to the modulation of phospholipase C (PLC), adenylyl cyclase, ion channels, and mitogen-activating protein kinases (MAP kinase), and eventually a variety of cellular and neuronal functions including neurotransmitter release. The fate of the delta receptor in the cell membrane is also well studied by Ping Yi Law, Horace Low, and colleagues. Similar to other G-protein-coupled receptors, upon the activation of delta receptor by its agonists, the receptor molecule can be internalized and degraded through endosomes, lysosomes, and proteosomes; some receptors may recycle back to the cell surface. Molecular components responsible for receptor trafficking have also been fully studied and documented in the literature.

The physiology and function of the delta receptor has slowly begun to emerge. It is now clear that activation of the receptor produces analgesia and antihyperalgesia. The latter seems especially important given changes in its trafficking and distribution during pathological pain states. Agonists at the delta receptor have been shown to act synergistically with those acting at the mu opioid receptor to produce enhanced states of antinociception with reduced side effect profiles. The co-administration of delta opioid agonists with mu opioid agonists inhibits the development of tolerance to the antinociceptive effect of mu opioid agonists.

Interactions between and among different types of opioid receptors have been documented in many in vivo and in vitro studies. The pharmacological significance of these interactions has also slowly emerged. Therapeutic indications beyond analgesia have emerged too. Delta agonists were recently shown by James Woods and his colleagues to possess antidepressant activity in animal models. The discovery of the presence of the delta receptor in cardiac myocytes led to the exploration by Garrett Gross and his colleagues of a cardioprotective role of the delta agonist against ischemic heart insults such as heart attacks. Other potential therapeutic applications are also implied for gastrointestinal disorders, bladder function, and immunomodulation. Availability of the pharmacophore structure of nonpeptide delta agonists such as BW373U86 and SNC80, and delta antagonists such as naltrindole, have facilitated the synthesis of a large number of new nonpeptide ligands. Explorations of the uses of these newly synthesized nonpeptide ligands in the previously mentioned potential therapeutic applications are underway. We are anticipating multiple major advances in the therapeutic applications of delta compounds in the future beyond analgesia.

This book is thus relevant to all with an interest in the delta receptor and receptor-related ligands, pharmacology, and physiology. We hope that it stimulates a broad readership in both the academic world and the pharmaceutical industry.

It would not have been possible to publish this book without the contributions of the authors of all the chapters, and we would like to express our thanks and gratitude to them.