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 α4β2
nAChR antagonists, with the tetrahydroisoquinolinium salts being more
potent than the parent tetrahydroisoquinoline derivatives. The most
potent α4β2 antagonist, 6c, exhibited submicromolar
binding Ki and functional IC50 values and high selectivity for this receptor over the α4β4
and α3β4 nAChRs. Whereas the (S)-6c enantiomer was essentially inactive at α4β2,
(R)-6c was a slightly more potent α4β2
antagonist than the reference β2-nAChR antagonist DHβΕ.
The observation that the α4β2 activity resided exclusively
in the (R)-enantiomer was in full agreement with
docking studies. Several of tetrahydroisoquinolinium salts also displayed
agonist activity at the α7 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 α4β2
nAChR antagonists for this indication.