Selective, nonpeptidic delta opioid receptor agonists have been the subject of great interest as potential novel analgesic agents. The discoveries of BW373U86 (1) and SNC80 (2) contributed to the rapid expansion of research in this field. However, poor drug-like properties and low therapeutic indices have prevented clinical evaluation of these agents. Doses of 1 and 2 similar to those required for analgesic activity produce convulsions in rodents and nonhuman primates. Recently, we described a novel series of potent, selective, and orally bioavailable delta opioid receptor agonists. The lead derivative, ADL5859 (4), is currently in phase II proof-of-concept studies for the management of pain. Further structure activity relationship exploration has led to the discovery of ADL5747 (36), which is approximately 50-fold more potent than 4 in an animal model of inflammatory pain. On the basis of its favorable efficacy, safety, and pharmacokinetic profile, 36 was selected as a clinical candidate for the treatment of pain.

8-Amino-2,6-methano-3-benzazocine derivatives have been made using Pd-catalyzed amination procedures, and their affinities for opioid receptors were assessed. The 8-amino group was hypothesized to be a replacement for the prototypic 8-OH substituent for 2,6-methano-3-benzazocines and related opiates. This OH group is generally required for binding yet is implicated in unfavorable pharmacokinetic characteristics such as low oral bioavailability and rapid clearance via O-glucuronidation. The core structures in which the 8-OH group was replaced were cyclazocine and its enantiomers, ethylketocyclazocine and its enantiomers, ketocyclazocine, and Mr2034. Many new analogues had high affinity for opioid receptors with several in the subnanomolar range. Highest affinity was seen in analogues with secondary 8-(hetero)arylamino appendages. Binding to opioid receptors was enantioselective with the (2R,6R,11R)-configuration preferred and high selectivity for mu and kappa over delta opioid receptors was observed within the series. Several derivatives were shown to have intrinsic opioid-receptor-mediated activity in [(35)S]GTPgammaS assays.

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A series of phosphorescent cyclometalated iridium complexes with 2,5-diphenylpyridine-based ligands has been synthesized and characterized to investigate the effect of the simple ligand modification on photophysics, thermostability and electrochemistry. The complexes have the general structure (C ∧ N) 2 Ir(acac), where C ∧ N is a monoanionic cyclometalating ligand [e.g. 2,5-diphenylpyridyl (dppy), 2,5-di(4-methoxyphenyl)pyridyl (dmoppy), 2,5-di(4-ethoxyphenyl)pyridyl (deoppy) and 2,5-di(4-ethylphenyl)pyridyl (deppy)]. The absorption, emission, cyclic voltammetry and thermostability of the complexes were systematically investigated. The (dppy) 2 Ir(acac) has been characterized using X-ray crystallography. Calculation on the electronic ground state of (dppy) 2 Ir(acac) was carried out using B3LYP density functional theory. The highest occupied molecular orbital (HOMO) level is a mixture of Ir and ligand orbitals, while the lowest occupied molecular orbital (LUMO) is predominantly dppy ligand-based. Electrochemical studies showed the oxidation potentials of (dmoppy) 2 Ir(acac), (deoppy) 2 Ir(acac), (deppy) 2 Ir(acac) were smaller than that of (ppy) 2 Ir(acac), while the oxidation potential of (dppy) 2 Ir(acac) was larger relative to (ppy) 2 Ir(acac). The 10% weight reduction temperatures of these complexes were above that of (ppy) 2 Ir(acac). All complexes exhibited intense green photoluminescence, which has been attributed to MLCT triplet emission. The maximum emission wavelengths in CH 2 Cl 2 at room temperature were in the range 531-544 nm, which is more red-shifted than that of (ppy) 2 Ir(acac).