Endogenous opioids have been studied extensively since their discovery, in
the hope of finding a perfect analgesic, devoid of the secondary effects of
alkaloid opioids. However, the design of selective opioid agonists has pro
ved very difficult. First, structural studies of peptides in general are ha
mpered by their intrinsic flexibility. Second, the relationship between con
stitution and the so-called 'bioactive conformation' is far from obvious. I
deally, a direct structural study of the complex between a peptide and its
receptor should,answer both questions, but such a study is not possible, be
cause opioid receptors are large membrane proteins, difficult to study by s
tandard structural techniques. Thus, conformational studies of opioid pepti
des are still important for drug design and also for indirect receptor mapp
ing. This review deals with conformational studies of natural opioid peptid
es in several solvents that mimic in part the different environments in whi
ch the peptides exert their action. None of the structural investigations y
ields a convincing bioactive conformation, but the global conformation of l
onger peptides in biomimetic environments can shed light on the interaction
with receptors.