Patent Evaluation: A New Class of 5-HT_1A Receptor Antagonists

Summary

Novelty: (S)-11-Hydroxy-10-methyl aporphine and processes for its preparation are claimed. The compound is a 5HT_1A antagonist. The (R)-isomer has previously been disclosed as a 5HT_1A agonist and the (S)-isomer is expected to be useful as an antidote for cocaine and as an appetite suppressant.

Biology: The (R)- and (S)-isomers had K_i versus [³H]-8-OH-DPAT binding in rat cortex homogenate of 3.1 and 39.0, respectively. Only the (S)-isomer was able to antagonize 8-OH-DPAT-induced inhibition of contractions of guinea pig ileum (ED₅₀ = 0.03 μM). Only the (R)-isomer was effective in inhibiting single shock-induced contractions of guinea pig ileum (ED₅₀ = 0.05 μM).

Chemistry: The synthesis of the (S)-isomer is exemplified. Resolution of the intermediate 11-methoxyaporphine by classical means is a key step.

Structure: