title: Stereoselective syntheses of the trans-decahydroquinoline-5-carboxylic acid epimers. Diastereomeric zwitterionic probes of gamma-aminobutyric acid related biological properties in vitro and in vivo.
abstract: The syntheses of the 5 beta and 5 alpha epimers of trans-(4a alpha,8a beta)-decahydroquinoline-5-carboxylic acids (3 and 4) from vinylogous bicyclic imide 10 are described. The reduction of trans-5-(1,3-dithian-2-ylidene)octahydro-2(1H)-quinolinone (13) to afford the 5 alpha-(1,3-dithian-2-yl) compound 16 was a key step in the synthesis of trans-4 while hydroboration-H2O2 treatment of phenylmethyl trans-octahydro-5-methylene-1(2H)-quinolinecarboxylate (21) to afford the 5 beta-hydroxymethyl compound 22 was a key step in the synthesis of 3. These trans diastereomers 3 and 4 and the previously prepared cis analogues 1 and 2 were investigated for their ability to interact with GABAA and GABAB receptors and picrotoxin binding sites as well as with neuronal GABA transport systems in brain tissue. Like 1 and 2, tonic-clonic seizures were induced when trans-3 or -4 were administered to mice intracerebroventricularly. Only trans-4 weakly inhibited [3H]GABA binding to GABAA and GABAB receptors in vitro. Large doses (10 mg/kg) of diazepam reversed the convulsant activity of both trans-3 and trans-4. Although trans-3 is the more potent convulsant, trans-4 may have GABA antagonist activity in vivo. However, none of the decahydroquinoline diastereomers have a pronounced effect on GABA receptors that can currently be studied in vitro. Results obtained in vivo lead us to propose that these diastereoisomers may serve as unique conformational probes relating certain zwitterionic topographies to stimulatory activity in the central nervous system.
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D000242:Cyclic AMP / Q000096:biosynthesis; D003975:Diazepam / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced; D013237:Stereoisomerism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D011804:Quinolines; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C037920:decahydroquinoline-5-carboxylic acid; D000242:Cyclic AMP; D003975:Diazepam