New small molecule fluorescent probes for G protein-coupled receptors: valuable tools for drug discovery.

G protein-coupled receptors (GPCRs) are essential signaling proteins and tractable therapeutic targets. To develop new drug candidates, GPCR drug discovery programs require versatile, sensitive pharmacological tools for ligand binding and compound screening. With the availability of new imaging modalities and proximity-based ligand binding technologies, fluorescent ligands offer many advantages and are increasingly being used, yet labeling small molecules remains considerably more challenging relative to peptides. Focusing on recent fluorescent small molecule studies for family A GPCRs, this review addresses some of the key challenges, synthesis approaches and structure-activity relationship considerations, and discusses advantages of using high-resolution GPCR structures to inform conjugation strategies. While no single approach guarantees successful labeling without loss of affinity or selectivity, the choice of fluorophore, linker type and site of attachment have proved to be critical factors that can significantly affect their utility in drug discovery programs, and as discussed, can sometimes lead to very unexpected results.

Buprenorphine in the workers' compensation setting.

Buprenorphine is approved by the Food and Drug Administration for the treatment of chronic pain in low-dose transdermal patch formulations and for the treatment of addiction in high-dose sublingual tablets and films. Clinicians often prescribe these high-dose preparations "off label" for pain management. In the workers' compensation setting, it is particularly important to consider factors such as a) if the injured person has, and is being treated for co-occurring addiction as well as pain; b) if alternative therapies, including opioid withdrawal, were considered prior to initiating buprenorphine treatment; and c) the anticipated duration of treatment. This article reviews buprenorphine's approved indications, formulations, pharmacology, clinical efficacy, and special considerations in the workers' compensation setting.

Functionalization of the 6,14-bridge of the orvinols. Part 3: preparation and pharmacological evaluation of 18- and 19-hydroxyl substituted orvinols.

The orvinols are a class of potent opioids which have been extensively studied, yet little is known about the effects of introducing substituents into the 18- and 19-positions. The etheno bridge of thevinone was hydroxylated to give both the 18- and 19-hydroxyl substituted thevinols. After 3-O-demethylation to the corresponding orvinols, binding and GTPgammaS functional assays indicated that hydroxyl substitution at the 18- and 19-positions differentially affects the mu opioid efficacy of orvinols.

Opioid ligands having delayed long-term antagonist activity: potential pharmacotherapies for opioid abuse.

Buprenorphine is a partial agonist at the micro -opioid receptor with long duration of action and also exhibits delayed antagonist activity. Buprenorphine is finding increasing use as a treatment agent for opioid abuse, though its low efficacy is not well tolerated by all addicts. There is interest in developing a higher efficacy version of buprenorphine and in this mini-review some of the ligands recently discovered, that share with buprenorphine a profile of agonism followed by delayed antagonism, are discussed.