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 combination of truncation of the galanin peptide along with N-and C-terminal modifications afforded analogs that suppressed seizures or pain following intraperitoneal administration. To generate orally-active galanin analogs, the previously reported lead compound Gal-B2 (NAX 5055) was redesigned by (1) central truncation, (2) introduction of D-amino acids, (3) and addition of backbone spacers. Analog D-Gal(7-Ahp)-B2, containing 7-amino heptanoic acid as a backbone spacer and oligo-D-lysine motif at the C-terminus, exhibited anticonvulsant and analgesic activity post intraperitoneal administration. Oral administration of D-Gal(7-Ahp)-B2 demonstrated analgesic activity with reduction in both acute and inflammatory pain in the mouse formalin model of pain at doses as low as 8 mg/kg.

Incorporation of Monodisperse Oligoethyleneglycol Amino Acids into Anticonvulsant Analogues of Galanin and Neuropeptide Y Provides Peripherally Acting Analgesics

“…The starting point for this project was our previous finding that an incorporation of lipoamino acids into GAL and NPY analogues yielded compounds that suppressed seizures in the brain. − Here, we hypothesized that replacing lipidation with dPEGylation will restrict penetration of the neuropeptide analogues into the brain, while their activities in the PNS would be retained. Since our initial SAR studies focused on dPEGylation of a well-characterized lead compound Gal-B2, we first describe a rational design and synthesis of Gal-B2-dPEG 24 that contains both a lipoamino acid and the dPEG 24 -lysine residue .…”

“…Anticonvulsant neuropeptides offer attractive templates to engineer peptide-based therapeutics for many neurological diseases . Previously, our group improved the central nervous system (CNS) bioavailability of neuropeptides galanin (GAL), neurotensin (NT), neuropeptide Y (NPY) and neuropeptide W (NPW) via a combination of lipidization and cationization that resulted in analogues that penetrated across the blood–brain barrier (BBB) yielding potent antiepileptic activities (Figure ). − Whereas GAL and NPY suppress epileptic seizures by binding to their respective receptors expressed within the brain, − both peptides are also thought to produce analgesia through their receptors expressed in the peripheral nervous system (PNS). − Galanin and its major receptors, subtype 1 (GalR1) and subtype 2 (GalR2), are expressed in sites of pain mediation outside the brain, including the dorsal root ganglion and the dorsal horn of the spinal cord . Both GalR1- and GalR2-preferring agonists produce inhibitory effects on nociception. ,− It is noteworthy that GalR3 may have less or no effects on peripheral antinociception activity, since low levels of GalR3 are found in both the dorsal root ganglion and spinal cord .…”

Targeting of relaxin-3 analogues to the brain for pharmacological modulation of neurosignalling

“…Placing the palmitoyl group at Ser10 of relaxin-3 B-chain (37) also showed a similar drop in binding to RXFP3 as 36, which could be a result of steric hindrance, where palmitoyl group in close proximity to Arg12 might prevent efficient interaction of Arg12 with RXFP3. It is evident that both spacer and lipid positions can impact on receptor binding similar to the observations made in the development of systemically stable liraglutide, semaglutide (Madsen et al, 2007;Lau et al, 2015) and galanin (Bulaj et al, 2008;Robertson et al, 2012). It should be noted however, that the competition binding assays were conducted in the presence of 1% BSA, as lack of BSA led to too high background reading from non-specific binding in the assays.…”

Beneficial effects of neuropeptide galanin on reinstatement of exercise‐induced somatic and psychological trauma

“…Antisense oligonucleotides to galanin can suppress axotomy‐induced upregulation of galanin‐like immunoreactivity in DRG neurons (Ji et al, ). On the other hand, endogenous galanin exhibits analgesic properties after combination with its receptors in the central and peripheral nervous systems (Robertson et al, ). Administration of galanin reduced both acute and chronic nociception as well as pain transmission in spinal cord and arcuate nucleus of the hypothalamus (Qinyang et al, ).…”