cis- and trans-2,3,3a,4,5,9b-Hexahydro-1H-benz[e]indoles: synthesis and evaluation of dopamine D2, and D3 receptor binding affinity

Xiaodong Song, Michael A. Crider, Sharon F. Cruse, Debasis Ghosh, Cheryl Klein-Stevens, Li Liang, Mark A. Scheideler, Annemarie Varming, Inger Søtofte

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cis- and trans-2,3,3a,4,5,9b-hexahydro-1H-benz [e]indoles were synthesized as conformationally rigid analogues of 3-phenylpyrrolidine and evaluated for dopamine (DA) D2S and D3 receptor binding affinity. The tricyclic benz[e]indole nucleus was constructed by a previously reported reductive amination-cyclization procedure. Several unexpectedside products were isolated and characterized using the general method. The trans-diastereoisomers exhibited greater affinities for the DA D3 receptor than the corresponding cis-isomers. In both the cis- and trans- series the greatest affinity for DA D3 receptors was shown by compounds substituted with N-n-propyl or N-allyl groups. The cis-(+-)-N-allyl derivative 21e demonstrated a D2S/D3 selectivity of 290. Resolution of cis-(+-)-5 and trans-(+-)- 21c into individual enantiomers showed that in both series the more active isomer had 3aR absolute configuration. These novel ligands may be useful tools for gaining additional information about the DA D3 receptor. Copyright Elsevier, Paris.dopamine / D2S receptor / D3 receptor / cis- and trans-2,3,3a,4,5,9b-hexahydro-1H-benz[e]indoles / receptor binding affinity.
Original languageEnglish
JournalEuropean Journal of Medicinal Chemistry
Pages (from-to)487-503
Publication statusPublished - 1999

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