[reaction: see text] We report that "activated" dimethyl sulfoxide efficiently dehydrogenates hydrazones to the respective diazo species at -78 degrees C. Under optimized conditions, triethylamine hydrochloride is removed quantitatively by vacuum filtration to provide solutions of diazo compounds. Stable diazo species can be isolated in high yield, or alternatively, the direct treatment of these solutions with carboxylic acids provides esters.

The pituitary adenylate cyclase-activating polypeptide (PACAP)-selective PAC1 receptor (PAC1R, ADCYAP1R1) is a member of the vasoactive intestinal peptide (VIP)/secretin/glucagon family of G protein-coupled receptors (GPCRs). PAC1R has been shown to play crucial roles in the central and peripheral nervous systems. The activation of PAC1R initiates diverse downstream signal transduction pathways, including adenylyl cyclase, phospholipase C, MEK/ERK and Akt pathways that regulate a number of physiological systems to maintain functional homeostasis. Accordingly, at times of tissue injury or insult, PACAP/PAC1R activation of these pathways can be trophic to blunt or delay apoptotic events and enhance cell survival. Enhancing PAC1R signaling under these conditions has the potential to mitigate cellular damages associated with cerebrovascular trauma (including stroke), neurodegeneration (such as Parkinson’s and Alzheimer’s disease) or peripheral organ insults. Conversely, maladaptive PACAP/PAC1R signaling has been implicated in a number of disorders, including stress-related psychopathologies (i.e., depression, posttraumatic stress disorder, and related abnormalities), chronic pain and migraine, and metabolic diseases; abrogating PAC1R signaling under these pathological conditions represent opportunities for therapeutic intervention. Given the diverse PAC1R-mediated biological activities, the receptor has emerged as a relevant pharmaceutical target. In this review, we first describe the current knowledge regarding the molecular structure, dynamics, and function of PAC1R. Then, we discuss the roles of PACAP and PAC1R in the activation of a variety of signaling cascades related to the physiology and diseases of the nervous system. Lastly, we examine current drug design and development of peptides and small molecules targeting PAC1R based on a number of structure-activity relationship studies and key pharmacophore elements. At present, the rational design of PAC1R-selective peptide or small-molecule therapeutics is largely hindered by the lack of structural information regarding PAC1R activation mechanisms, the PACAP-PAC1R interface, and the core segments involved in receptor activation. Understanding the molecular basis governing the PACAP interactions with its different cognate receptors will undoubtedly provide a basis for the development and/or refinement of receptor-selective therapeutics.

Vinyl cations, generated by reacting β-hydroxy-α-diazo ketones with Lewis acids, undergo a 1,2-shift and C–H insertion to give cyclopentenone products.

The G protein-coupled pituitary adenylate cyclase-activating polypeptide receptor (PAC1R) is a potential therapeutic target for endocrine, metabolic and stress-related disorders. However, many questions regarding the protein structure and dynamics of PAC1R remain largely unanswered. Using microsecond-long simulations, we examined the open and closed PAC1R conformations interconnected within an ensemble of transitional states. The open-to-closed transition can be initiated by “unzipping” the extracellular domain and the transmembrane domain, mediated by a unique segment within the β3-β4 loop. Transitions between different conformational states range between microseconds to milliseconds, which clearly implicate allosteric effects propagating from the extracellular face of the receptor to the intracellular G protein-binding site. Such allosteric dynamics provides structural and mechanistic insights for the activation and modulation of PAC1R and related class B receptors.