Conformation-activity relationships of opioid peptides with selective activities at opioid receptors

The discovery of endogenous opioid peptides 25 years ago opened up a new ch apter in efforts to understand the origins and control of pain, its relatio nships to other biological functions, including inflammatory and other, imm une responses, and the relationships of opioid peptides and their receptors to a variety of undesirable or toxic side effects often associated with th e nonpeptide opiates such as morphine including addiction, constipation, a variety of neural toxicities, tolerance, and respiratory depression. For th ese investigations the need for potent and highly receptor selective agonis ts and antagonists has been crucial since they in principle allow one to di stinguish unequivocally the roles of the different opioid receptors (mu, de lta, and kappa) in the various biological and pathological roles of the opi oid peptides and their receptors. Conformational and topographical constrai nt aint of the linear natural endogenous opioid peptides has played a major role in developing peptide ligands with high selectivity for mu, delta, an d kappa receptors, and in understanding the conformational, topographical, and stereoelectronic structural requirements of the opioid peptides for the ir interactions with opioid receptors. in turn, this had led to insights in to the three-dimensional pharmacophore for opioid receptors. In this articl e we review and discuss some of the developments that have led to potent, s elective, and stable peptide and peptidomimetic ligands that are highly pot ent and selective, and that have delta agonist, mu antagonist, and kappa ag onist biological activities (other authors in this issue will discuss the d evelopment of other types of activities and selectivities). These have led to ligands that provide unique insight into opioid pharmacophores and the c ritical roles opioid ligands and receptor scan play in pain, addiction, and other human maladies. (C) 2000 John Wiley & Sons, Inc.