Patent Evaluation: Novel GABA Autoreceptor Antagonists

Summary

Novelty: Novel 1-substituted-1,2,3,4-tetrahydroisoquinolines are claimed. A method of treating CNS disorders such as anxiety, depression or psychoses by the administration of such compounds is also claimed. The compounds are GABA autoreceptor antagonists which have little activity at the GABA_A receptor itself.

Biology: Compounds were tested for their ability to block agonist-induced inhibition of potassium-evoked GABA-release from rat cortex in vitro (a measure of GABA autoreceptor antagonism), and to antagonize agonist-induced depolarization of isolated rat vagus nerve (a measure of GABA_A antagonism). In the former test pA₂ values quoted range from 5.2 to 9.2.

Chemistry: Twenty-two compounds are exemplified by synthesis. [1RS,2'SR]-1-(2-Tetrahydrofuranyl)-1,2,3,4-tetrahydroisoquinoline is one of twelve specifically claimed compounds.

Structure: