title: Identification of novel ligands for the gabapentin binding site on the alpha2delta subunit of a calcium channel and their evaluation as anticonvulsant agents.
abstract: As part of a program to investigate the structure-activity relationships of Gabapentin (Neurontin), a number of alkylated analogues were synthesized and evaluated in vitro for binding to the Gabapentin binding site located on the alpha2delta subunit of a calcium channel. A number of other bridged and heterocyclic analogues are also reported along with their in vitro data. Two compounds showing higher affinity than Gabapentin were selected for evaluation in an animal model of epilepsy. One of these compounds, cis-(1S,3R)-(1-(aminomethyl)-3-methylcyclohexyl)acetic acid hydrochloride (19), was shown to be effective in this model with a profile similar to that of Gabapentin itself.
authors.affiliation: Parke Davis Neuroscience Research Centre, Cambridge University Forvie Site, Robinson Way, Cambridge CB2 2QB, U.K.
authors.forename: J S
authors.initials: JS
authors.lastname: Bryans
authors.forename: N
authors.initials: N
authors.lastname: Davies
authors.forename: N S
authors.initials: NS
authors.lastname: Gee
authors.forename: V U
authors.initials: VU
authors.lastname: Dissanayake
authors.forename: G S
authors.initials: GS
authors.lastname: Ratcliffe
authors.forename: D C
authors.initials: DC
authors.lastname: Horwell
authors.forename: C O
authors.initials: CO
authors.lastname: Kneen
authors.forename: A I
authors.initials: AI
authors.lastname: Morrell
authors.forename: R J
authors.initials: RJ
authors.lastname: Oles
authors.forename: J C
authors.initials: JC
authors.lastname: O'Toole
authors.forename: G M
authors.initials: GM
authors.lastname: Perkins
authors.forename: L
authors.initials: L
authors.lastname: Singh
authors.forename: N
authors.initials: N
authors.lastname: Suman-Chauhan
authors.forename: J A
authors.initials: JA
authors.lastname: O'Neill
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D000588:Amines; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D001665:Binding Sites; D015220:Calcium Channels / Q000378:metabolism*; D003509:Cyclohexanecarboxylic Acids; D003510:Cyclohexanes; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy; D000077206:Gabapentin; D008024:Ligands; D008297:Male; D051379:Mice; D012663:Semicarbazides / Q000633:toxicity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid
chemical_list: C112420:(1-(aminomethyl)-3-methylcyclohexyl)acetic acid; D000085:Acetates; D000588:Amines; D000927:Anticonvulsants; D015220:Calcium Channels; D003509:Cyclohexanecarboxylic Acids; D003510:Cyclohexanes; D008024:Ligands; D012663:Semicarbazides; C010059:carbamylhydrazine; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin