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

cis- and trans-2,3,3a,4,5,9b-Hexahydro-1H-benz[e]indoles were synthesized a s conformationally rigid analogues of 3-phenylpyrrolidine and evaluated for dopamine (DA) D-2S and D-3 receptor binding affinity. The tricyclic benz[e ]indole nucleus was constructed by a previously reported reductive aminatio n-cyclization procedure. Several unexpected side products were isolated and characterized using the general method. The trans-diastereoisomers exhibit ed greater affinities for the DA D-3 receptor than the corresponding cis-is omers. In both the cis- and trans- series the greatest affinity for DA D-3 receptors was shown by compounds substituted with N-n propyl or N-allyl gro ups. The cis-(+/-)-N-allyl derivative 21e demonstrated a D-2S /D-3 selectiv ity of 290. Resolution of cis-(+/-)-5 and trans-(+/-)-21c into individual e nantiomers showed that in both series the more active isomer had 3aR absolu te configuration. These novel Ligands may be useful tools for gaining addit ional information about the DA D-3 receptor. (C) Elsevier, Paris.