Synthesis and Serotonin Binding Site Studies of Some Conformationally Restricted Indolylethylamine Analogues Based on 2-Amino-3-(3'-indolyl)bicyclooctane

Article abstract of DOI:10.1021/jm00163a062

The bicycloannulation reaction between cyclohexanone and indolyl enamines yields trans-3-(cyclic amino)-2-(3'-indolyl)bicyclo<2.2.2>octan-5-ones, and these adducts are conformationally restricted analogues of indolylethylamine (tryptamine) which exhibit structure-dependent affinity for the serotonin 5HT₂ and 5HT_1a receptors.The stereochemistry of the isomeric endo and exo adduct obtained is assigned from the 1H NMR spectra of the specifically deuterated alkenes prepared from the ketones by the Bamford-Stevens reaction.Molecular mechanics calculations indicate that the conformational flexibility of the amino and indolyl groups is restricted through van der Waals interactions with the bridges of the bicyclic unit.These compounds inhibit the binding of <3H>ketanserin to 5HT₂ sites in mouse cerebrocortical membranes, and the binding of <3H>-8-hydroxy-2-(di-n-propylamino)tetralin(<3H>-8-OH-DPAT) to 5HT_1a sites in mouse hippocampal membranes.The endo compounds are the most potent, and molecular mechanics calculations indicate that these isomers have a less bulky bicyclo bridge proximate to the amine group and more conformational freedom about the C_α-C_β-N⁺-H dihedral angle (τ³).In the 5HT₂ assay, endo-trans-3-(N-piperidinyl)-2-(3'-indolyl)bicyclo<2.2.2>octan-5-one (10a) is the most potent, and endo-trans-3-(N-pyrrolidinyl)-2-(3'-indolyl)bicyclo<2.2.2>oct-5-ene (12a) is the most potent in the 5HT_1a assay.A phenyl-substituted adduct shows the least affinity in these two assays.These data provide insight into the structural differences between the 5HT_1a and 5HT₂ receptor sites.