Replacement of the lost myelin sheath is a therapeutic goal for treating demyelinating diseases of the central nervous system (CNS), such as multiple sclerosis (MS). The G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptor (GPCR) GPR17, which is phylogenetically closely related to receptors of the “purinergic cluster,” has emerged as a modulator of CNS myelination. However, whether GPR17-mediated signaling positively or negatively regulates this critical process is unresolved. We identified a small-molecule agonist, MDL29,951, that selectively activated GPR17 even in a complex environment of endogenous purinergic receptors in primary oligodendrocytes. MDL29,951-stimulated GPR17 engaged the entire set of intracellular adaptor proteins for GPCRs: G proteins of the Gαi, Gαs, and Gαq subfamily, as well as β-arrestins. This was visualized as alterations in the concentrations of cyclic adenosine monophosphate and inositol phosphate, increased Ca2+ flux, phosphorylation of extracellular signal–regulated kinases 1 and 2 (ERK1/2), as well as multifeatured cell activation recorded with label-free dynamic mass redistribution and impedance biosensors. MDL29,951 inhibited the maturation of primary oligodendrocytes from heterozygous but not GPR17 knockout mice in culture, as well as in cerebellar slices from 4-day-old wild-type mice. Because GPCRs are attractive targets for therapeutic intervention, inhibiting GPR17 emerges as therapeutic strategy to relieve the oligodendrocyte maturation block and promote myelin repair in MS.

Adenosine receptors belong to the family of G protein-coupled receptors. Four distinct subtypes are known, termed A(1), A(2A), A(2B) and A(3). Adenosine is an important signaling molecule which is released under inflammatory conditions. It can show antiinflammatory as well as proinflammatory activities, and the contribution of the specific adenosine receptor subtypes in various cells, tissues and organs is complex. Agonists selective for adenosine A(1) receptors show antinociceptive activity and are active in animal models of neuropathic and inflammatory pain. Adenosine A(2A) receptor agonists are potent antiinflammatory drugs. A(2A)-selective antagonists have shown antihyperalgesic activity in animal models of inflammatory pain. For A(2B)agonists as well as A(2B) antagonists antiinflammatory activity has been postulated. Selective A(2B) antagonists were shown to decrease (inflammatory) pain, and are promising candidates for the treatment of asthma. Adenosine A(3) receptor agonists appear to be proinflammatory, while there is evidence for an antiinflammatory effect of A(3) antagonists. There are some contradictory findings, and A(3) agonists are being developed for the treatment of inflammatory diseases such as arthritis. Indirect mechanisms increasing the extracellular concentration of adenosine using adenosine kinase inhibitors, adenosine deaminase inhibitors or adenosine uptake inhibitors, or increasing the potency of adenosine at the A(1) receptor subtype by allosteric modulators lead to potent antinociceptive and antiinflammatory activity. The advantage of indirectly acting drugs may be their site- and event-specific action since they are only active where adenosine has been released. In the past decade considerable progress has been made towards the identification of novel lead structures and the development of potent and selective ligands for all four adenosine receptor subtypes. A large number of patents has recently been filed and the field is finally in the process of translating many years of basic science into therapeutic application. This review article will focus on compounds published or patented within the past three years.

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The preparation of a new optically active alcohol with a carboxylic function that allowed its attachment to an amine-functionalized insoluble polymer is described. Its first use as a polymer supported chiral auxiliary is demonstrated by asymmetric transformation of two racemic aryl propionic acids via ketene formation (95-96% ee).