title: Anticonvulsant neuropeptides as drug leads for neurological diseases.
abstract: Anticonvulsant neuropeptides are best known for their ability to suppress seizures and modulate pain pathways. Galanin, neuropeptide Y, somatostatin, neurotensin, dynorphin, among others, have been validated as potential first-in-class anti-epileptic or/and analgesic compounds in animal models of epilepsy and pain, but their therapeutic potential extends to other neurological indications, including neurodegenerative and psychatric disorders. Disease-modifying properties of neuropeptides make them even more attractive templates for developing new-generation neurotherapeutics. Arguably, efforts to transform this class of neuropeptides into drugs have been limited compared to those for other bioactive peptides. Key challenges in developing neuropeptide-based anticonvulsants are: to engineer optimal receptor-subtype selectivity, to improve metabolic stability and to enhance their bioavailability, including penetration across the blood–brain barrier (BBB). Here, we summarize advances toward developing systemically active and CNS-penetrant neuropeptide analogs. Two main objectives of this review are: (1) to provide an overview of structural and pharmacological properties for selected anticonvulsant neuropeptides and their analogs and (2) to encourage broader efforts to convert these endogenous natural products into drug leads for pain, epilepsy and other neurological diseases.
authors.affiliation: College of Pharmacy, Department of Medicinal Chemistry, 421 Wakara Way, STE. 360 Salt Lake City, UT 84108, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Robertson
authors.forename: Sean P
authors.initials: SP
authors.lastname: Flynn
authors.forename: H Steve
authors.initials: HS
authors.lastname: White
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Bulaj
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism / Q000627:therapeutic use; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000378:metabolism; D004399:Dynorphins / Q000378:metabolism / Q000627:therapeutic use; D004827:Epilepsy / Q000188:drug therapy; D019004:Galanin / Q000378:metabolism / Q000627:therapeutic use; D015394:Molecular Structure; D009422:Nervous System Diseases / Q000188:drug therapy*; D009478:Neuropeptide Y / Q000378:metabolism / Q000627:therapeutic use; D009479:Neuropeptides / Q000378:metabolism / Q000627:therapeutic use; D009496:Neurotensin / Q000378:metabolism / Q000627:therapeutic use; D012640:Seizures / Q000188:drug therapy; D017386:Sequence Homology, Amino Acid; D013004:Somatostatin / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D000701:Analgesics, Opioid; D000927:Anticonvulsants; D009478:Neuropeptide Y; D009479:Neuropeptides; D009496:Neurotensin; D013004:Somatostatin; D004399:Dynorphins; D019004:Galanin