ici-174865 and naltrindole

We synthesized derivatives of the δ opioid receptor (DOR) antagonists naltrindole (NTI) and compound 1 that were modified with small alkyl or fluorinated ethyl substituents on the 17-nitrogen. Although the derivatives showed decreased binding affinities for the opioid receptors, their selectivities for the DOR were higher than the parent compounds NTI and compound 1. Surprisingly, 17-fluoroethyl NTI derivatives exerted DOR inverse agonistic activities. The DOR inverse agonism of compounds 4c-e was less efficacious but significant, as compared with a standard DOR inverse agonist ICI-174864. On the other hand, compound 1 and its derivatives with small alkyl or monofluoroethyl substituents were partial agonists, but the derivatives having di- or trifluoroethyl group showed neither agonistic nor inverse agonistic activities.

Topics: Drug Inverse Agonism; Enkephalin, Leucine; Halogenation; Humans; Naltrexone; Narcotic Antagonists; Receptors, Opioid, delta; Recombinant Proteins

A series of naltrindole-related ligands (4-10) with an N-methyl,N-phenethyl,N-cinnamyl, or an unsubstituted basic nitrogen were synthesized and tested for opioid agonist and antagonist activity in smooth muscle preparations and in mice. The nor compounds (4 and 6) and the phenethyl derivatives (5 and 8) displayed full agonist activity (IC50 = 85-179 nM) in the mouse vas deferens preparation (MVD) while the other members of the series exhibited partial agonist or weak antagonist activity. In the guinea pig ileum preparation (GPI), all compounds except 8 were partial agonists. The ligands that were evaluated in mice were found to produce antinociception that was not selectively mediated via delta opioid receptors. However, two of these ligands (4 and 5) appeared to be delta-selective opioid receptor antagonists at subthreshold doses for antinociception. The finding that all of the compounds bind selectively to delta opioid receptors in guinea pig brain membranes together with the in vitro pharmacology and in vivo antagonist studies suggests that the lack of delta agonist selectivity in vivo may be due to a number of factors, including a basic difference between the delta receptor system in the MVD and in the mouse brain. Further, it is suggested that the constellation of message and address components in the morphindole nucleus may tend to stabilize delta receptors in the brain in antagonist state.

Topics: Analgesia; Animals; Guinea Pigs; Indoles; Male; Mice; Morphinans; Muscle, Smooth; Naltrexone; Narcotic Antagonists; Receptors, Opioid, delta; Structure-Activity Relationship

Approaches to the design of peptidomimetic ligands are currently of great interest because of the discovery of an increasing number of endogenous peptides that modulate physiological processes. The inherent lability of peptides and their poor oral absorption have made peptidomimetics attractive targets for drug development. In this presentation I have discussed the design of a novel series of delta-selective opioid antagonists based on the message-address concept. The opioid peptides can be viewed to contain two elements: an essential message component that is recognized by the receptor subsite responsible for the signal transduction process and an address element that is recognized by a subsite that is unique to a single receptor type and functions to enhance binding to the site. Since the tyramine moiety in opiate structures is known to be important for activity, an identical element in Tyr1 of the opioid peptides can be viewed as the message. A key moiety of the delta address was considered to be the phenyl group of Phe4. Combining the universal opioid antagonist naltrexone (5) with a strategically located address mimic afforded naltrindole (6, NTI), the first nonpeptide delta opioid receptor antagonist.

Topics: Amino Acid Sequence; Drug Design; Enkephalins; Indoles; Molecular Sequence Data; Morphinans; Naltrexone; Protein Conformation; Receptors, Opioid; Receptors, Opioid, delta; Structure-Activity Relationship

Highly selective nonpeptide ligands with potent delta opioid receptor antagonist activity have been developed using the message-address concept. This approach envisaged the delta opioid receptor to contain two major recognition subsites; a message subsite which recognizes the pharmacophore, and an address subsite that is unique for the delta receptor type and confers selectivity. The message and address components of the delta-selective enkephalins were postulated to be Tyr1 and Phe4, respectively, with Gly2-Gly3 functioning as a spacer. The message component of the target compounds in this study was derived from naltrexone and related structures. An indole system was fused to the C ring of naltrexone as a mimic of the address component. The benzene moiety of indole was viewed as the delta address component, mimicking the phenyl group of Phe4, and the pyrrole portion was used as a rigid spacer. Members of the series (1-23) were evaluated for opioid antagonist activity on the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. Naltrindole (NTI, 1) was the most potent member of the series, with Ke values of approximately 0.1 nM at delta receptors. The antagonism by NTI was approximately 220- and 350-fold greater at delta than at mu and kappa opioid receptors. The binding of NTI and selected members of the series to guinea pig brain membranes was qualitatively consistent with their pharmacologic antagonist activity profiles in the MVD and GPI, but the Ki values were not in the same rank order. The selectivity of NTI arises mainly as a consequence of increased affinity at delta receptors. Thus, the Ke and Ki values of NTI were 1/530 and 1/90 that of the delta antagonist enkephalin analogue, ICI 174864. In contrast to NTI, ICI174864 derives its selectivity through greatly decreased recognition at mu and kappa receptors. The implications of the high affinity and selectivity of NTI as a consequence of its conformational rigidity are discussed. It is suggested that any attempt to model a receptor-bound conformation of an opioid peptide should consider affinity and potency at multiple receptor sites rather than selectivity alone.

Topics: Animals; Computer Simulation; Drug Design; Guinea Pigs; In Vitro Techniques; Indoles; Mice; Morphinans; Muscle, Smooth; Naltrexone; Narcotic Antagonists; Receptors, Opioid, delta; Structure-Activity Relationship