Synthesis of hexahydrocyclopenta[ij]isoquinolines as a new class of dopaminergic agents

• A new synthesis of the 1,2,3,7,8,8a-hexahydrocyclopenta [ij]isoquinoline skeleton.
• 5,6-Dioxygenated-7-phenyl-HCPIQs synthesized by Friedel–Crafts cyclization with Eaton's reagent.
• Catecholic HCPIQs showed nanomolar affinity towards D2 dopamine receptors.
• Catecholic HCPIQs displayed a remarkable selectivity and lack of cytotoxicity.
• HCPIQs show high potential in the treatment of Parkinson's disease, psychosis or depression.

In this study, we have described the synthesis of the tricyclic 1,2,3,7,8,8a-hexahydrocyclopenta [ij]isoquinoline (HCPIQ). Herein, six differently substituted 5,6-dioxygenated-7-phenyl-HCPIQs have been synthesized using a new methodology via (E)-1-styryl-THIQ by Friedel–Crafts cyclization with Eaton's reagent. Results showed that HCPIQs (3, 3a–e) displayed a moderate affinity for D1 dopamine receptors (DR) in the micromolar range, furthermore the catecholic HCPIQs 3a (NH), 3c (NCH3) and 3e (NCH2CHCH2) exhibited outstanding affinity and high selectivity towards D2 DR. Indeed, 3a, 3c and 3e showed Ki values of 29 nM, 13 nM and 18 nM, respectively, and HCPIQs 3a (NH) and 3c (NCH3) displayed a remarkable selectivity (Ki D1/D2 ratio ∼ 1000–2500). In addition, none of the catecholic compounds showed any cytotoxicity in freshly isolated human neutrophils. Although further studies are needed, these compounds and particularly catecholic HCPIQs, show high potential in the treatment of Parkinson's disease, psychosis or depression.

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