Design and Synthesis of 4‑Heteroaryl 1,2,3,4-Tetrahydroisoquinolines as Triple Reuptake Inhibitors

A series of 4-bicyclic heteroaryl 1,2,3,4-tetrahydroisoquinoline inhibitors of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) was discovered. The synthesis and structure–activity relationship (SAR) of these triple reuptake inhibitors (TRIs) will be discussed. Compound <b>10i</b> (AMR-2), a very potent inhibitor of SERT, NET, and DAT, showed efficacy in the rat forced-swim and mouse tail suspension models with minimum effective doses of 0.3 and 1 mg/kg (<i>po</i>), respectively. At efficacious doses in these assays, <b>10i</b> exhibited substantial occupancy levels at the three transporters in both rat and mouse brain. The study of the metabolism of <b>10i</b> revealed the formation of a significant active metabolite, compound <b>13</b>

Design and Synthesis of a New Series of 4‑Heteroarylamino-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octanes as α7 Nicotinic Receptor Agonists. 1. Development of Pharmacophore and Early Structure–Activity Relationship

The design and synthesis of a series of quinuclidine-containing spirooxazolidines (“spiroimidates”) and their utility as α7 nicotinic acetylcholine receptor partial agonists are described. Selected members of the series demonstrated excellent selectivity for α7 over the highly homologous 5-HT_3A receptor. Modification of the <i>N</i>-spiroimidate heterocycle substituent led to (1<i>S</i>,2<i>R</i>,4<i>S</i>)-<i>N</i>-isoquinolin-3-yl)-4′<i>H</i>-4-azaspiro­[bicyclo­[2.2.2]­octane-2,5′oxazol]-2′-amine (BMS-902483), a potent α7 partial agonist, which improved cognition in preclinical rodent models