Synthesis of Novel GABA Uptake Inhibitors. 3. Diaryloxime and Diarylvinyl Ether Derivatives of Nipecotic Acid and Guvacine as Anticonvulsant Agents1

1999 ◽  
Vol 42 (18) ◽  
pp. 3447-3462 ◽  
Author(s):  
Lars J. S. Knutsen ◽  
Knud Erik Andersen ◽  
Jesper Lau ◽  
Behrend F. Lundt ◽  
Rodger F. Henry ◽  
...  
Keyword(s):  
Gaba Uptake ◽  
Nipecotic Acid ◽  
Uptake Inhibitors ◽  
Derivatives Of ◽  
Gaba Uptake Inhibitors

Synthesis and biological evaluation of new derivatives of 2-substituted 4-hydroxybutanamides as GABA uptake inhibitors

2011 ◽  
Vol 46 (1) ◽  
pp. 183-190 ◽  
Author(s):  
Katarzyna Kulig ◽  
Krzysztof Więckowski ◽  
Anna Więckowska ◽  
Justyna Gajda ◽  
Bartłomiej Pochwat ◽  
...  
Keyword(s):  
Biological Evaluation ◽  
Gaba Uptake ◽  
Uptake Inhibitors ◽  
Synthesis And Biological Evaluation ◽  
Derivatives Of ◽  
Gaba Uptake Inhibitors

Synthesis of 4,4-bis(2-methylphenyl)-3-butenyl (and butyl) analogs of 4-phenyl-1,4- and 6-phenyl-1,6-dihydropyridine-3-carboxylic acids and their evaluation as neuronal GABA-uptake inhibitors

1997 ◽  
Vol 75 (6) ◽  
pp. 601-610 ◽  
Author(s):  
Nadeem Iqbal ◽  
Zhong-Yong Wei ◽  
Glen B. Baker ◽  
Edward E. Knaus
Keyword(s):  
Catalytic Amount ◽  
Gaba Uptake ◽  
Methyl Nicotinate ◽  
Decomposition Products ◽  
Nipecotic Acid ◽  
Reference Drug ◽  
Uptake Inhibitors ◽  
Ester Moiety ◽  
Gaba Uptake Inhibitors

Treatment of 3-[2-(4,4-dimethyl-4,5-dihydrooxazolin-2-yl)]-4-phenyl-1,4-dihydropyridine (13) with NaH–DMSO, and then reaction with 1,1-bis(2-methylphenyl)-4-bromobutane (12c) afforded 1-[4,4-bis(2-methylphenyl)butyl]-3-[2-(4,4-dimethyl-4,5-dihydrooxazolin-2-yl)]-4-phenyl-1,4-dihydropyridine (14). Reaction of methyl nicotinate with 2.1 equivalents 12c or 1,1-bis(2-methylphenyl)-4-bromo-1-butene (11b) afforded 4,4-bis(2-methylphenyl)butyl 1-[4,4-bis(2-methylphenyl)butyl]pyridinium-3-carboxylate bromide (17) or 4,4-bis(2-methylphenyl)-3-butenyl 1-[4,4-bis(2-methylphenyl)-3-butenyl]pyridinium-3-carboxylate bromide (18), respectively. The nonregioselective reaction of the pyridinium salts (17/18) with PhMgCl in THF at −23 °C using a catalytic amount of CuI afforded a mixture of isomeric 4-phenyl-1,4-dihydropyridyl (21 or 22) and 6-phenyl-1,6-dihydropyridyl (27 or 28) products in a ratio of approximately 1:1. All attempts to hydrolyze the 4,4-bis(2-methylphenyl)butyl or 3-butenyl ester moiety of 21/22 or 27/28 to a carboxyl group resulted in decomposition products. In contrast, the corresponding 3-(2-cyanoethyl) esters (23, 24, 29, 30) were readily converted to the corresponding carboxyl analogs (25, 26, 31, 32) via a β-elimination reaction of acrylonitrile using the non-nucleophilic base DBU. The 4-phenyl-1,4-dihydropyridyl (14, 25, 26) and 6-phenyl-1,6-dihydropyridyl (27/28 or 31/32) compounds inhibited the in vitro uptake of [3H]GABA into striatal prisms in the 21–44% range at a 10−4 M test compound concentration, relative to the reference drug nipecotic acid (87% inhibition). Structure–activity correlations showed the dihydropyridyl C-3 substituent was a determinant of [3H]GABA uptake where the potency order was CO2H > 2-(4,4-dimethyl-4,5-dihydrooxazolin-2-yl) > CO2(CH2)3CH-(o-tolyl)2 and CO2(CH2)2CH=C-(o-tolyl)2. Compounds possessing C-3 and (or) N-1 CO2(CH2)3CH-(o-tolyl)2 substituents were generally more potent than analogs having CO2(CH2)2CH=C-(o-tolyl)2 substituents. In general, 1,6-dihydropyridyl compounds were more potent than the corresponding 1,4-dihydropyridyl isomers. Keywords: 1,4- and 1,6-dihydropyridines, GABA-uptake inhibitors.

Synthesis of 4-substituted nipecotic acid derivatives and their evaluation as potential GABA uptake inhibitors

2016 ◽  
Vol 24 (9) ◽  
pp. 2072-2096 ◽  
Author(s):  
Tim Hellenbrand ◽  
Georg Höfner ◽  
Thomas Wein ◽  
Klaus T. Wanner
Keyword(s):  
Gaba Uptake ◽  
Nipecotic Acid ◽  
Uptake Inhibitors ◽  
Gaba Uptake Inhibitors

Synthesis and Biochemical Studies of Spirocyclic Amino Acid Esters, Part 3 Activity of 2-Azaspiro[4.5]decane-6-carboxylates as GABA-Uptake Inhibitors

1996 ◽  
Vol 329 (3) ◽  
pp. 149-154 ◽  
Author(s):  
Wilhelm Fleischhacker ◽  
Silvia Lauritz ◽  
Ernst Urban ◽  
Peter Baumann ◽  
Helmut Bittiger
Keyword(s):  
Amino Acid ◽  
Gaba Uptake ◽  
Amino Acid Esters ◽  
Uptake Inhibitors ◽  
Biochemical Studies ◽  
Gaba Uptake Inhibitors ◽  
Acid Esters
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