Chemistry Of Opioids

Recent Advances in the Synthesis of Morphine and Related Alkaloids; by N. Chida * Opioids in Preclinical and Clinical Trials; by H. Nagase and H. Fujii * Synthesis of 14-Alkoxymorphinan Derivatives and Their Pharmacological Actions; by H. Schmidhammer and M. Spetea * 14-Amino-4,5-Epoxymorphinan Derivatives and Their Pharmacological Actions; by J. W. Lewis and S. M. Husbands * Nonpeptidic Delta (δ) Opioid Agonists and Antagonists of the Diarylmethylpiperazine Class: What Have We Learned?; by S. N. Calderon * Synthesis of Neoclerodane Diterpenes and Their Pharmacological Effects; by K. M. Lovell, K. M. Prevatt-Smith, A. Lozama and T. E. Prisinzano * Synthesis of Novel Basic Skeletons Derived from Naltrexone; by H. Nagase and H. Fujii * Twin and Triplet Drugs in Opioid Research; by H. Fujii * 3D-Pharmacophore Identification for κ-Opioid Agonists Using Ligand-Based Drug-Design Techniques; by N. Yamaotsu and S. Hirono

The rapidly burgeoning research of the past two decades on agonist-antagonist analgesics and opioid receptors makes this exhaustive review of opioid anal gesics particularly relevant and timely. After an introductory chapter the additional 12 chapters begin logically with morphine and congeners (4- epoxymorphinans) and end with opioid receptors. All principal chemical types of centrally acting analgesics (including endogenous opioid-like substances) and their antagonists as well as the mixed agonist-antagonists are treated thoroughly, although not always (and for good reason) in historical (chrono logical) order. A chapter on miscellaneous types (atypical structures for the most part) includes the benzimidazoles (etonitazene), aminotetralins (dezocine), tetrahydroisoquinolines (methopholine), and so on. Important aspects and correlations of chemistry, pharmacology, and biochemistry are discussed in depth. Literature citations are numerous. For educators, practicing laboratory scientists, and physicians, this scholarly review by two authors well of opioid analgesics versed in the chemistry, pharmacology, and biochemistry will be informative, stimulating, and thought-provoking. Everette L. May Medical College of Virginia Richmond, VA 23298 v Preface The history of opium predates the written word, although knowledge of its constituents dates back less than 200 years. Over the centuries its popularity for the relief of pain has waxed and waned, until today the opiates are widely recognized as excellent analgesics but with disadvantages that have impaired their use seriously. There is a clear need for a potent analgesic with minimal effects on the respiratory centers and gastrointestinal tract and preferably devoid of dependence liability.

Recent Advances in the Synthesis of Morphine and Related Alkaloids; by N. Chida * Opioids in Preclinical and Clinical Trials; by H. Nagase and H. Fujii * Synthesis of 14-Alkoxymorphinan Derivatives and Their Pharmacological Actions; by H. Schmidhammer and M. Spetea * 14-Amino-4,5-Epoxymorphinan Derivatives and Their Pharmacological Actions; by J. W. Lewis and S. M. Husbands * Nonpeptidic Delta (δ) Opioid Agonists and Antagonists of the Diarylmethylpiperazine Class: What Have We Learned?; by S. N. Calderon * Synthesis of Neoclerodane Diterpenes and Their Pharmacological Effects; by K. M. Lovell, K. M. Prevatt-Smith, A. Lozama and T. E. Prisinzano * Synthesis of Novel Basic Skeletons Derived from Naltrexone; by H. Nagase and H. Fujii * Twin and Triplet Drugs in Opioid Research; by H. Fujii * 3D-Pharmacophore Identification for κ-Opioid Agonists Using Ligand-Based Drug-Design Techniques; by N. Yamaotsu and S. Hirono

The interest in opioids such as morphine, the prototypical opioid ligand, has been maintained through the years. The identification of endogenous opioids and their receptors (mu, delta, kappa, and nociceptin), molecular cloning, and the elucidation of the crystal structures of opioid receptors represent key milestones in opioid research. The opioid system modulates numerous pharmacological responses, with therapeutic (i.e., analgesia) and detrimental side effects (i.e., addiction). The medical use and misuse of opioids have dramatically increased, leading to the 21st century opioid crisis. This book presents recent developments in opioid drug discovery, specifically in the medicinal chemistry and pharmacology of new ligands targeting the opioid receptors as effective and safe therapeutics for human diseases. Furthermore, it draws a special attention to advancing concepts and strategies in opioid drug discovery to mitigate opioid liabilities. The diversity among the discussed topics is a testimony to the complexity of the opioid system, which results from the expression, regulation, and functional role of ligands and receptors. The array of multidisciplinary research areas illustrates the rapidly developing basic research and translational activities in opioid drug discovery. This book will serve as a useful reference while also stimulating continued research in the chemistry and pharmacology of opioids and their receptors, with the prospect of developing improved therapies for human diseases, but also improving health and quality of life in general.

Opioids such as morphine, codeine, and oxycodone are extracts or analogs isolated from a single source: the opium poppy. For a long time, it was believed to be nature's only source of opioids. But it now appears that biological diversity has evolved an alternative source of opioid compounds-those derived from the plant Mitragyna speciosa. This plan

This Brief takes the reader on a chemical journey by following the history for over two centuries of how an opiate became an opioid, thus spawning an empire and a series of crises. These imperfect resemblances of alkaloids are both natural and synthetic substances that, particularly in America, are continually part of a growing concern about overuse. This seemed an inviting prospect for those in pain, but as the ubiquitous media coverage continues to lay bare, the levels of abuse point to the fact that perhaps an epidemic is upon us, if not a culture war. Seeking answers to how and why this addiction crisis transpired over two hundred years of long development, this Brief examines the role that the chemistry laboratory played in turning patients into consumers. By utilizing a host of diverse sources, this Brief seeks to trace the design and the production of opioids and their antecedents over the past two centuries. From the isolation and development of the first alkaloids with morphine that relieved pain within the home and on the battlefield, to the widespread use of nostrums and the addiction crisis that ensued, to the dissemination of drugs by what became known as Big Pharma after the World Wars; and finally, to competition from home-made pharmaceuticals, the progenitor was always, in some form, a type of chemistry lab. At times, the laboratory pressed science to think deeply about society's maladies, such as curing disease and alleviating pain, in order to look for new opportunities in the name of progress. Despite the best intentions opioids have created a paradox of pain as they were manipulated by creating relief with synthetic precision and influencing a dystopian vision. Thus, influence came in many forms, from governments, from the medical community, and from the entrepreneurial aspirations of the general populace. For better, but mostly for worse, all played a role in changing forever the trajectory of what started with the isolation of a compound in Germany. Combining chemistry and history in a rousing new long-form narrative that even broadens the definition of a laboratory, the origins and future of this complicated topic are carefully examined.

"This monograph is based upon papers and discussion from the technical review on the medicinal chemistry and molecular pharmacology of opioid peptides and the opiates which took place on September 4-6, 1984, at Bethesda, Maryland. The meeting was sponsored by the Office of Science and the Division of Preclinical Research, National Institute on Drug Abuse. The papers on molecular pharmacology, biosynthesis, and analysis of opioid peptides are presented in this volume. Those on the medical chemistry of opioid peptides appear in NIDA Research Monograph 69" [entitled Opioid peptides : medicinal chemistry] -- page iv.