γ-Carbolines: a novel class of cannabinoid agonists with high aqueous solubility and restricted CNS penetration.

An oral, peripherally restricted CB1/CB2 agonist could provide an interesting approach to treat chronic pain by harnessing the analgesic properties of cannabinoids but without the well-known central side effects. γ-Carbolines are a novel class of potent mixed CB1/CB2 agonists characterized by attractive physicochemical properties including high aqueous solubility. Optimization of the series has led to the discovery of 29, which has oral activity in a rat inflammatory pain model and limited brain exposure at analgesic doses, consistent with a lower risk of CNS-mediated tolerability issues.

Delta agonist hydroxy bioisosteres: the discovery of 3-((1-benzylpiperidin-4-yl){4-[(diethylamino)carbonyl]phenyl}amino)benzamide with improved delta agonist activity and in vitro metabolic stability.

We have investigated phenol replacements in a series of diaryl amino piperidine delta opioid agonists. From this study we have demonstrated that the hydroxy functional group can be replaced with a primary amide group, giving enhanced activity at the delta receptor, increased selectivity versus mu and kappa as well as improved in vitro metabolic stability.

N,N-Diethyl-4-[(3-hydroxyphenyl)(piperidin-4-yl)amino] benzamide derivatives: the development of diaryl amino piperidines as potent delta opioid receptor agonists with in vivo anti-nociceptive activity in rodent models.

We have investigated a series of phenolic diaryl amino piperidine delta opioid receptor agonists, establishing the importance of the phenol functional group and substitution on the piperdine nitrogen for delta agonist activity and selectivity versus the mu and kappa opioid receptors. This study uncovered compounds with improved agonist potency and selectivity compared to the standard, non-peptidic delta agonist SNC-80. In vivo anti-nociceptive activity of analog 8e in two rodent models is discussed, demonstrating the potential of delta agonists to provide a novel mechanism for pain relief.

Novel benzimidazole derivatives as selective CB2 agonists.

The preparation and evaluation of a novel class of CB2 agonists based on a benzimidazole moiety are reported. They showed binding affinities up to 1nM towards the CB2 receptor with partial to full agonist potencies. They also demonstrated good to excellent selectivity (>1000-fold) over the CB1 receptor.