Potent anticonflict activity and lessening of memory impairment with a series of novel [1]benzothieno[2,3-c]pyridines and 1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridines.
[1]Benzothieno[2,3-c]pyridines (10a-c, 11, 12a-t, and 13a,b) and 1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridines (3a-c, 7, 8a-c, and 9) were synthesized. The compounds are bioisosteres of beta-carbolines and 1,2,3,4-tetrahydro-beta-carbolines where the indole nitrogen is replaced by sulfur. Their pharmacological activity was evaluated in a water lick conflict test in rats and a passive avoidance test in mice. In the 1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridine series, the presence of ethyl ester (3b) or cyclohexyl carboxamide (7) groups at C-3 conferred good anticonflict activity and lessening of memory impairment, while N-acylation of 3b abolished activity. In the [1]benzothieno(2,3-c]pyridine series, the aminoethyl carboxamide (12a) group at C-3 also conferred activity, but other amides studied were not active. The most potent compounds (3b, 7, and 12a) were also administered orally and had potent anticonflict and antiscopolamine amnesia-reversal activity. These compounds did not bind to the BZP receptor in spite of having structures similar to those of beta-carbolines. Compound 7 bound strongly to 5-HT1A receptors and would be expected to be a novel anxiolytic.
Kawakubo
H
H
Department of Medicinal Chemistry, Asahi Chemical Industry Company, Ltd., Miyazaki, Japan.
Okazaki
K
K
Nagatani
T
T
Takao
K
K
Hasimoto
S
S
Sugihara
T
T
D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D003220:Conflict, Psychological; D008297:Male; D008568:Memory / Q000187:drug effects*; D051379:Mice; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D058924:Thienopyridines
D014151:Anti-Anxiety Agents; D011725:Pyridines; D011963:Receptors, GABA-A; D011985:Receptors, Serotonin; D013440:Sulfides; D058924:Thienopyridines; C066285:N-cyclohexyl-1,2,3,4-tetrahydro(1)benzothieno(2,3-c)pyridine-3-carboxamide