Alkanes adopt extended conformations in solution that minimize steric interactions and maximize surface area. Folding can reduce the amount of hydrophobic surface exposed to solvent, but sterically unfavorable gauche interactions result. However, we found that the alkyl chains of two common surfactants in aqueous solution adopt helical conformations when bound within a synthetic receptor. The receptor recognizes the helical alkane better than the extended conformation, even though 2 to 3 kilocalories per mole of strain is introduced. The proper filling of space and burial of hydrophobic surface drive the molecular recognition between the receptor and the coiled alkane.

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 testedin vitroandin vivofor its affinity and efficacy at galanin receptors. Galmic has micromolar affinity for GalR1 receptors (K_i= 34.2 μM) 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.