Synthesis of novel gamma-aminobutyric acid (GABA) uptake inhibitors. 5.(1) Preparation and structure-activity studies of tricyclic analogues of known GABA uptake inhibitors.
On the basis of the SAR of a series of known gamma-aminobutyric acid (GABA) uptake inhibitors, including 4 (SKF 89976), new tricyclic analogues have been prepared. These novel compounds are derivatives of nipecotic acid, guvacine, and homo-beta-proline, substituted at the nitrogen of these amino acids by various lipophilic moieties such as (10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)alkoxyalkyl or (10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)alkoxyalkyl. The in vitro values for inhibition of [(3)H]-GABA uptake in rat synaptosomes was determined for each compound in this new series, and it was found that several of the novel compounds showed a high potency comparable with that of the reference compounds 4, 5 (tiagabine), and 6 (CI-966). Several of the novel compounds were also evaluated for their ability in vivo to inhibit clonic seizures induced by a 15 mg/kg (ip) dose of methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). One compound, (R)-1-(2-(2-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)ethoxy)ethyl)-3-piperidinecarboxylic acid (23), was selected for further biological investigations and showed a protective index comparable to or slightly better than that of the recently launched anticonvulsant product 5 ((R)-1-(4,4-bis(3-methyl-2-thienyl)-3-butenyl)-3-piperidinecarboxylic acid).
Andersen
K E
KE
Health Care Discovery, Novo Nordisk A/S, Novo Nordisk Park, DK 2760 Måløv, Denmark. kea@novo.dk
Sørensen
J L
JL
Lau
J
J
Lundt
B F
BF
Petersen
H
H
Huusfeldt
P O
PO
Suzdak
P D
PD
Swedberg
M D
MD
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000737:chemistry* / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects; D002243:Carbolines; D003292:Convulsants; D005260:Female; D051379:Mice; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000927:Anticonvulsants; D000929:Antidepressive Agents, Tricyclic; D002243:Carbolines; D003292:Convulsants; D014179:Neurotransmitter Uptake Inhibitors; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D005680:gamma-Aminobutyric Acid