The opiate receptor: a model explaining structure-activity relationships of opiate agonists and antagonists.

Abstract

A model of the opiate receptor is proposed which explains structure-activity relationships of opiate drugs, including (l) the unique potency of certain opiates such as etonitazene, fentanyl, phenazocine, and oripavines; (ih) the role of N-allyl substituents in conferring antagonist properties; and (iii) chemical features that afford "pure" antagonists. The model indicates molecular mechanisms for interconversion of the opiate receptor between respective states that bind agonists or antagonists with high affinity. Unique pharmacological properties of many opiates are not readily explained by their chemical structures. Examples include (i) the great potency of opiates such as etonitazene, fentanyl, phenazocine, and etorphine (Fig. 1); (ii) the dramatic change from agonist to antagonist effects conferred by transforming an opiate N-methyl to an N-allyl or related substituent; and (iii) the chemical features determining that "pure" opiate antagonists such as naloxone lack analgesic and euphoric actions while "mixed" agonist-antagonists possess both.Studies on opiate receptor binding differentiate agonists and antagonists (1). The opiate receptor appears to exist in two interconvertible forms, one with uniquely high affinity for antagonists and the other with selective affinity for agonists (2). Sodium ions enhance antagonist and depress agonist binding presumably by regulating interconversion of the two opiate receptor states, while manganese selectively facilitates agonist binding (2,3). These influences may physiologically regulate interactions of the opiate receptor with the naturally occurring, morphine-like peptide, enkephalin (4-7).Here we suggest possible conformations of opiates at their receptor site which can explain similarities in pharmacological actions of compounds whose chemical structures appear, superficially, quite different. A model of opiate receptor function is proposed specifying conformational changes that underlie the interconversion of the two receptor states and explaining the pharmacological differences of opiate agonists and antagonists.

Molecular Structure of Two Conformationally Restrained Fentanyl Analogues: cis- and trans-isomers of N-{3-Methyl-1-[2-(1,2,3,4-tetrahydro)naphthyl]-4-piperidinyl}-N-phenylpropanamide

“…This contradicts another model derived from molecular models which suggested a "folded" fentanyl conformation where the orientation of a phenyl ring of the phenethyl group is equivalent to the orientation of the comparable phenyl ring in other, more rigid, opiates. 23 The piperidine ring in both the cis-and trans-isomers exists in a chair conformation with the 4-propanilido group extended and equatorially oriented. This is also the case in the crystal structure of fentanyl24 itself and a 4-methoxymethyl derivative of fentanyl which shows analgetic activity 460 times that of fentanyl.25 The N-acyl functions in all four of these compounds are essentially planar with nearly perpendicular dihedral angles between the N-acyl plane and the plane of the N-phenyl ring (fentanyl, 89"; 2a, 87.9", 2b, 93.3'; and 4-CHzOCH3-fentanyl, 85").…”

ADRENOCORTICOTROPHIC HORMONE FRAGMENTS MIMIC THE EFFECT OF MORPHINE in vitro

“…In view of the model proposed for opiate receptors by Feinberg, Creese & Snijder (1976), it is tempting to speculate that 3 and j receptors differ with respect to lipophilic binding sites and that ACTH fragments bind to these sites of the 3 receptor and to the amino binding site of the opioid receptor.…”

Kinetic Studies in Isolated Organs: Tools to Design Analgesic Peptides and to Analyze Their Receptor Effects

“…The first one is the quality and the relative orienta tion of C-6 substituent in the morphine back bone (8,24) or that of the parent substituents in synthetic narcotics. The other one is the presence of the 'second' benzene ring in an appropriate position (6). Compounds suitable to check the sensitivity of MVD preparation to the functional moieties mentioned above, were tested.…”