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A little light release: Temporarily blocked (“caged”) dG nucleosides that can be incorporated into oligodeoxynucleotides are presented (see figure). Their hydrogen‐bond‐recognition site is inaccessible in the inactive form; this prevents, for example, the formation of secondary structures. Light can trigger the release of the unmodified oligonucleotide and thus induce correct folding.

The pharmacological exploitation of the galanin receptors as drug targets for treatment of epilepsy, depression, and pain has been hampered by the lack of workable compounds for medicinal chemists from random screening of large chemical libraries. The present work uses the tripeptidomimetic galnon and displays its presumed pharmacophores on a rigid molecular scaffold. The scaffold is related to marine natural products and presents three functional groups near one another in space, in a manner reminiscent of a protein surface. An active compound, Galmic, was identified from a small synthetic library and tested in vitro and in vivo for its affinity and efficacy at galanin receptors. Galmic has micromolar affinity for GalR1 receptors (K i ‫؍‬ 34.2 M) and virtually no affinity for GalR2 receptors. In vitro, Galmic, like galanin, suppresses long-term potentiation in the dentate gyrus; it blocks status epilepticus when injected intrahippocampally or administered i.p. Galmic applied i.p. shows antidepressant-like effects in the forced-swim test, and it is a potent inhibitor of flinching behavior in the inflammatory pain model induced by formalin injection. These data further implicate brain and spinal cord galanin receptors as drug targets and provide an example of a systemically active compound based on a scaffold that mimics protein surfaces.G alanin, a 29-to 30-aa-long neuropeptide, has been shown to affect feeding, cognitive, and sexual behavior and to regulate seizure and pain thresholds when applied intraventricularly (1-3). Galanin actions are mediated through three G proteincoupled receptors present in the brain and the peripheral nervous system (4-6). Transgenic mice overexpressing galanin have much higher seizure thresholds (7), and the galanin receptor 1 (GalR1) Ϫ/Ϫ mice have spontaneous seizures, demonstrating the role of galanin and its receptor in seizure control (8). Despite the wealth of biological information on galanin signaling, no progress has been made in using the galanin-receptor subtypes as drug targets. The lack of progress is largely due to the poor results from random screening at several major pharmaceutical companies (9). More than 4 million compounds were screened, but no workable compounds for medicinal chemical optimization were identified. Both Johnson & Johnson (10) and Schering have published reports of compounds active at high micromolar concentrations that had stability problems, as well as other problems (9). The only nonpeptide galanin receptor ligand available is galnon, a substance intended to display analogs of the three major pharmacophores of galanin, Trp-2, Asn-5, and Tyr-9 (11, 12), on a linear, peptide-like backbone. Galnon is a lowaffinity, nonreceptor-subtype-selective agonist that acts at both GalR1-and GalR2-type receptors (13). Despite its serious shortcomings, galnon, within a year of its synthesis, was shown to affect behavioral symptoms and neurochemical correlates in opiate withdrawal (14), pain (15), and seizure (13) The present work describes the synthesis and ...

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