Generating Orally Active Galanin Analogues with Analgesic Activities

Abstract

The endogenous neuropeptide galanin has anticonvulsant and analgesic properties mediated by galanin receptors expressed in the central and peripheral nervous systems. Our previous work showed that by combining truncation of the galanin peptide with N- and C-terminal modifications afforded analogues that suppress seizures or pain upon intraperitoneal (i.p.) administration. To generate orally active galanin analogues, the previously reported lead compound Gal-B2 (NAX 5055) was redesigned by 1) central truncation, (2) introduction of D-amino acids, and 3) addition of backbone spacers. Analogue D-Gal(7-Ahp)-B2, containing 7-aminoheptanoic acid as a backbone spacer and an oligo-D-lysine motif at the C terminus, exhibits anticonvulsant and analgesic activity post-i.p. administration. Oral administration of D-Gal(7-Ahp)-B2 demonstrates analgesic activity with decreases in both acute and inflammatory pain in the mouse formalin model of pain at doses as low as 8 mg kg⁻¹.