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Paper | Regular issue | Vol 87, No. 3, 2013, pp.551-558
Published online, 5th February, 2013
DOI: 10.3987/COM-12-12574
■ Synthesis and Biological Activity of Novel Heterocyclic Ring Systems: Imidazo[4’,5’:3,4]pyrido[2,1-a]isoquinolines and Imidazo[4,5-f][3]benzazecines

Robert Otto, Christoph Enzensperger, and Jochen Lehmann*

*Institute of Pharmacy, Friedrich-Schiller-University, Philosophenweg 14, 07743 Jena, Germany

Abstract

Derivatives of two novel heterocyclic ring systems were synthesized and their affinities for dopamine receptors were measured. The compounds were obtained by reacting histamine with 2-(2-bromoethyl)benzaldehyde including an atypical Pictet-Spengler condensation, which afforded basic and not the usual neutral or acidic conditions. The resulting imidazo[4',5':3,4]pyrido[2,1-a]-isoquinoline derivative 4 was Boc protected at the most basic imidazole nitrogen, the isoquinoline nitrogen then quaternized by using methyl iodide and the tetracyclic isoquinolinium salt was both deprotected and cleaved under Birch conditions in one step to give a tricyclic imidazo[4,5-f][3]benzazecine derivative (3) by opening two 6-membered heterocycles towards one 10-membered. Radioligand binding studies showed a significant affinity of the moderately constrained 3 but not of 4 for dopamine receptors. Similar to the analogous indolo-benzazecine LE300, a preference of 3 for the D1 receptor family was observed, but with some loss of affinity over all.