Modern approaches to the development of synthetic cannabinoid receptor probes.

The endocannabinoid system, which spans the central and peripheral nervous systems and regulates many biologic processes, is an important target for probe discovery and medications development. Whereas the earliest endocannabinoid receptor probes were derivatives of the non-selective phytocannabinoids isolated from Cannabis species, modern drug discovery techniques have expanded the definitions of what constitutes a CB1R or CB2R cannabinoid receptor ligand. This review highlights recent advances in synthetic cannabinoid receptor chemistry and pharmacology. We provide examples of new CB1R- and CB2R-selective probes, and discuss rational approaches to the design of peripherally-restricted agents. We also describe structural classes of positive- and negative allosteric modulators (PAMs and NAMs) of CB1R and CB2R. Finally, we introduce new opportunities for cannabinoid receptor probe development that have emerged in recent years, including biased agonists that may lead to medications lacking adverse effects.

Cellular signaling and gene expression profiles evoked by a bivalent macrocyclic peptide that serves as an artificial MET receptor agonist.

Non-native ligands for growth factor receptors that are generated by chemical synthesis are applicable to therapeutics. However, non-native ligands often regulate cellular signaling and biological responses in a different manner than native ligands. Generation of surrogate ligands comparable to native ligands is a challenging need. Here we investigated changes in signal transduction and gene expression evoked by a bivalent macrocyclic peptide (aMD5-PEG11) capable of high-affinity binding to the MET/hepatocyte growth factor (HGF) receptor. Binding of aMD5-PEG11 to the MET extracellular region was abolished by deletion of the IPT3-IPT4 domain, indicating the involvement of IPT3-IPT4 in the binding of aMD5-PEG11 to the MET receptor. aMD5-PEG11 induced dimerization and activation of the MET receptor and promoted cell migration that was comparable to induction of these activities by HGF. Signal activation profiles indicated that aMD5-PEG11 induced phosphorylation of intracellular signaling molecules, with a similar intensity and time dependency as HGF. In 3-D culture, aMD5-PEG11 as well as HGF induced epithelial tubulogenesis and up-regulated the same sets of functionally classified genes involved in multicellular organism development. Thus, a non-native surrogate ligand that consisted of a bivalent macrocyclic peptide can serve as an artificial MET receptor agonist that functionally substitutes for the native ligand, HGF.