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Modulators of S1P1 have proven utility for the treatment of autoimmune disease and efforts to identify new agents with improved safety and pharmacokinetic parameters are ongoing. Several new S1P1 chemotypes were designed and optimized for potency and oral bioavailability. These new agents are characterized by a 'tricyclic fused indole array' and are highly potent agonists of the S1P1 receptor., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The cannabinoid receptor type 2 (CB2) is a class A GPCR that was cloned in 1993 while looking for an alternative receptor that could explain the pharmacological properties of Δ(9)-tetrahydrocannabinol. CB2 was identified among cDNAs based on its similarity in amino acid sequence to the CB1 receptor and helped provide an explanation for the established effects of cannabinoids on the immune system. In addition to the immune system, CB2 has widespread tissue expression and has been found in brain, peripheral nervous system, and gastrointestinal tract. Several "mixed" cannabinoid agonists are currently in clinical use primarily for controlling pain, and it is believed that selective CB2 agonism may afford a superior analgesic agent devoid of the centrally mediated CB1 effects. Thus, selective CB2 receptor agonists represent high value putative therapeutics for treating pain and other disease states. In this Perspective, we seek to provide a concise update of progress in the field.