Synthesis of Novel γ-Aminobutyric Acid (GABA) Uptake Inhibitors. 5. Preparation and Structure−Activity Studies of Tricyclic Analogues of Known GABA Uptake Inhibitors

Abstract

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).

Self‐Assembly of Semifluorinated Dendrons Attached to Electron‐Donor Groups Mediates Their π‐Stacking via a Helical Pyramidal Column

“…The commercially available phenothiazine (6) was sublimed and used immediately for the synthesis of the electron-donating 2-(phenothiazine-10-yl-ethoxy)ethanol (8). The latter was prepared in 53 % yield according to a modified literature procedure [12] by the alkylation of phenothiazine (6) with THP-protected 2-(2-chloroethoxy)ethanol (7). In addition to the carbazole linked to diethylene glycol spacer (2EO) reported previously, [8b] the synthesis of a car- bazole derivative attached to a tetraethylene glycol spacer (4EO) was also achieved.…”

“…Phenothiazine (6, 98 %, Aldrich) was dissolved in Et 2 O to filter off green oxidation products before recrystallization from EtOH and subsequent sublimation. 3,4,12,12,11,11,10,10,9,9,8,8,7,7,6,6,5,5-heptadecafluoro-n-dodecyloxy)benzoic acid (12), [10a] 1-bromo -12,12,12,11,11,10,10,9,9,8,8,7,7,6,6,5,5-heptadecafluoron-dodecane (2),…”

“…(D4), {2-[2-((1-pyrenyl)acetoxy)ethoxy]ethyl}3,4,5-tris- (12,12,12,11,11,10,10,9,9,8,8,7,7,6,6,5,5-heptadecafluoro-n-dodecan-1-yloxy)benzoate A C H T U N G T R E N N U N G (3,4,5)12F8G1-2EOPy (D7) and [4-(1-pyrenyl)-butyl] 3,4,5-tris- (12,12,12,11,11,10,10,9,9,8,8,7,7,6,6,5,5-hepta-decafluoron-dodecan-1-yloxy)benzoate A C H T U N G T R E N N U N G (3,4,5)12F8G1-BuPy (D6) has been described previously.…”

“…The mixture was heated at 80 8C for 16 h. JA C H T U N G T R E N N U N G (H,H) = 4.7 Hz, 2 H; ArOCH 2 CH 2 ), 3.84 (m, 2 H; CH 2 ), 3.75 (m,8 H;overlap OCH 3 and CH 2 ), 3.66 (t, 3 JA C H T U N G T R E N N U N G (H,H) = 4.7 Hz, 2 H; CH 2 ), 2.35 (br s, 1 H; OH); 13 C NMR (CDCl 3 ,125 MHz,20 8C): d = 161.9,160.9,94.7,94.0,93.8,73.0,70.0,67.8,67.5,62.1,55.7,55.6 1, 150.3, 89.6, 88.0, 72.9, 70.4, 67.6, 62.3, 48.2, 25.9 2-(2-Phenothiazine-10-yl-ethoxy)ethanol (8): Compound 8 was prepared using a modified literature procedure. [12] Phenothiazine 6 (3.8 g, 19 mmol) and NaH (1.5 g, 37.5 mmol; 60 % suspension in mineral oil) were added to of dry, freshly distilled dibutyl ether (30 mL). The mixture was heated at 135 8C for 60 min under N 2 .…”

Tiagabine is neuroprotective in the N171-82Q and R6/2 mouse models of Huntington's disease

“…Nipecotic acid does not cross the blood brain barrier efficiently, however. We therefore tested its derivative tiagabine, which has an attached lipophilic group that enables the drug to cross the blood-brain barrier (Andersen et al, 2001;Krogsgaard-Larsen et al, 2000) in HD mouse models.…”