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Lawrence H. Lazarus,¹ Sharon D. Bryant,¹ Martti Attila,² and Severo Salvadori³

¹Laboratory of Environmental Neuroscience, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 USA; ²Department of Pharmacy, University of Helsinki, SF-00014 Helsinki, Finland; ³Department of Pharmaceutical Science, University of Ferrara, I-44100 Ferrara, Italy

Abstract
Naturally occurring environmental substances often mimic endogenous substances found in mammals and are capable of interacting with specific proteins, such as receptors, with a high degree of fidelity and selectivity. Narcotic alkaloids and amphibian skin secretions, introduced into human society through close association with plants and animals through folk medicine and religious divination practices, were incorporated into the armamentarium of the early pharmacopoeia. These skin secretions contain a myriad of potent bioactive substances, including alkaloids, biogenic amines, peptides, enzymes, mucus, and toxins (noxious compounds notwithstanding) ; each class exhibits a broad range of characteristic properties. One specific group of peptides, the opioids, containing the dermorphins (dermal morphinelike substances) and the deltorphins (-selective opioids) , display remarkable analgesic properties and include an amino acid with the rare (in a mammalian context) D-enantiomer in lieu of the normal L-isomer. Synthesis of numerous stereospecific analogues and conformational analyses of these peptides provided essential insights into the tertiary composition and microenvironment of the receptor "pocket" and the optimal interactions between receptor and ligand that trigger a biological response ; new advances in the synthesis and receptor-binding properties of the deltorphins are discussed in detail. These receptor-specific opioid peptides act as more than mimics of endogenous opioids: their high selectivity for either the µ or receptor makes them formidable environmentally derived agents in the search for new antagonists for treating opiate addiction and in the treatment of a wide variety of human disorders. Key words: amphibians, deltorphin, dermorphin, evolution, mimicry, molecular modeling, opiate addiction, opioid peptides, peptide synthesis. Environ Health Perspect 102:648-654 (1994)

Address correspondence to L. H. Lazarus, NIEHS, PO Box 12233, MD C3-04, Research Triangle Park, NC 27709 USA.

S. Salvadori was supported by grants from CNR Progetto Finalizzato Chimica Fine e Secondaria II and Murst. We are indebted to our Italian collaborators at both the University of Ferrara, Ferrara, Italy, and P. A. Temussi, T. Tancredi, and their associates in the University of Naples, Naples, Italy ; to James E. Huff and Joseph T. Wachsman for their suggestions during the preparation of this article, Joel Casey and Jack Field for their computer expertise, Kenneth Jefferies for assistance in collecting rat brains, Elizabeth West for her artistic talents in preparing the figures, and the anonymous reviewers for their critical evaluation of the manuscript. We further and most gratefully appreciate the invaluable librarians, in particular Ralph J. Hester and Frances T. Lyndon, who provided us with publications from obscure journals, innumerable articles, and current literature searches.

Received 24 February 1994 ; accepted 23 May 1994.