title: Design, synthesis, and pharmacological characterization of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): a potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties.
abstract: 2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (9) was designed as a conformationally constrained analog of glutamic acid. For 9, the key torsion angles (tau 1 and tau 2) which determine the relative positions of the alpha-amino acid and distal carboxyl functionalities are constrained where tau 1 = 166.9 degrees or 202 degrees and tau 2 = 156 degrees, respectively. We hypothesized that 9 would closely approximate the proposed bioactive conformation of glutamate when acting at group 2 metabotropic glutamate receptors (mGluRs). The racemic target molecule (+/-)-9, its C2-diastereomer (+/-)-16, and its enantiomers (+)-9 (LY354740) and (-)-9 (LY366563) were prepared by an efficient, stereocontrolled, and high-yielding synthesis from 2-cyclopentenone. Our hypothesis that 9 could interact with high affinity and specificity at group 2 mGluRs has been supported by the observation that (+/-)-9 (EC50 = 0.086 +/- 0.025 microM) and its enantiomer (+)-9 (EC50 = 0.055 +/- 0.017 microM) are highly potent agonists for group 2 mGluRs in the rat cerebral cortical slice preparation (suppression of forskolin-stimulated cAMP formation) possessing no activity at other glutamate receptor sites (iGluR or group 1 mGluR) at concentrations up to 100 microM. Importantly, the mGluR agonist effects of (+)-9 are evident following oral administration in mice in both the elevated plus maze model of anxiety (ED50 = 0.5 mg/kg) and in the ACPD-induced limbic seizure model (ED50 = 45.6 mg/kg). Thus, (+)-9 is the first orally active group 2 mGluR agonist described thus far and is an important tool for studying the effects of compounds of this class in humans.
authors.affiliation: Central Nervous System Division, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. Monn@Lilly.com
authors.forename: J A
authors.initials: JA
authors.lastname: Monn
authors.forename: M J
authors.initials: MJ
authors.lastname: Valli
authors.forename: S M
authors.initials: SM
authors.lastname: Massey
authors.forename: R A
authors.initials: RA
authors.lastname: Wright
authors.forename: C R
authors.initials: CR
authors.lastname: Salhoff
authors.forename: B G
authors.initials: BG
authors.lastname: Johnson
authors.forename: T
authors.initials: T
authors.lastname: Howe
authors.forename: C A
authors.initials: CA
authors.lastname: Alt
authors.forename: G A
authors.initials: GA
authors.lastname: Rhodes
authors.forename: R L
authors.initials: RL
authors.lastname: Robey
authors.forename: K R
authors.initials: KR
authors.lastname: Griffey
authors.forename: J P
authors.initials: JP
authors.lastname: Tizzano
authors.forename: M J
authors.initials: MJ
authors.lastname: Kallman
authors.forename: D R
authors.initials: DR
authors.lastname: Helton
authors.forename: D D
authors.initials: DD
authors.lastname: Schoepp
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D015195:Drug Design; D018690:Excitatory Amino Acid Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D051381:Rats; D017470:Receptors, Glutamate / Q000378:metabolism*
chemical_list: D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D001643:Bridged Bicyclo Compounds; D018690:Excitatory Amino Acid Agonists; D017470:Receptors, Glutamate; D005576:Colforsin; D000242:Cyclic AMP; C104753:eglumetad