Dual Nicotinic Acetylcholine Receptor α4β2 Antagonists/α7 Agonists: Synthesis, Docking Studies, and Pharmacological Evaluation of Tetrahydroisoquinolines and Tetrahydroisoquinolinium Salts

We describe the synthesis of tetrahydroisoquinolines and tetrahydroisoquinolinium salts together with their pharmacological properties at various nicotinic acetylcholine receptors. In general, the compounds were alpha 4 beta 2 nAChR antagonists, with the tetrahydroisoquinolinium salts being more potent than the parent tetrahydroisoquinoline derivatives. The most potent alpha 4 beta 2 antagonist, 6c, exhibited submicromolar binding K-i and functional IC50 values and high selectivity for this receptor over the alpha 4 beta 4 and alpha 4 beta 4 nAChRs. Whereas the (S)-6c enantiomer was essentially inactive at alpha 4 beta 2, (R)-6c was a slightly more potent alpha 4 beta 4 antagonist than the reference beta 2-nAChR antagonist DH beta E. The observation that the alpha 4 beta 2 activity resided exclusively in the (R)-enantiomer was in full agreement with docking studies. Several of tetrahydroisoquinolinium salts, also displayed agonist activity at the alpha 7 nAChR. Preliminary in vivo evaluation revealed antidepressant-like effects of both (R)-5c and (R)-6c in the mouse forced swim test, supporting the therapeutic potential of alpha 4 beta 2 nAChR antagonists for this indication.