Conformationally and rotationally restricted analogs of 5-hydroxytryptamine

Abstract

The ethylamino side chain of serotonin can assume many conformations due to unrestricted rotation about its two dihedral angles. The synthesis of rigid analogs of serotonin with rotational restriction of the side chain could lead to increased activity and/or selectivity at serotonin receptors. Derivatives 8, 9 and 10 substituted at the 4-position of indole were sought as well as the bicyclo derivatives 11, 12 and 13 substituted at the 3-position. The bicyclo derivative 11 was prepared by the direct condensation of the ketone precursor (quinuclidinone) with 5-methoxyindole under basic conditions. The reaction is thought to proceed through an intermediate similar to structure 32. This procedure results in the formation of the olefin which can then be reduced to the desired compound. The derivatives substituted at the 4-position were prepared via halogen-metal exchange reactions. Beginning with the 4-bromo derivative of indole and the appropriate piperidone derivative, compounds 37, 38 and 39 were generated. Birch reduction of the intermediate tertiary alcohol was necessary to derive the final compounds. Syntheses of 12 and 13 also utilized the halogen-metal exchange reaction. Direct condensation under basic conditions, as was utilized in the synthesis of 11, was unsuccessful, possibly due to the formation of a double bond within a 5-membered ring, as seen in the [2.2.1] bicyclo derivative. Thus, the halogen-metal exchange reaction of the 3-bromo, derivative of indole with the bicyclo derivative 22 and 26 yielded the tertiary alcohols 40 and 41 respectively. Molecular modeling of the bicyclo compounds showed a 4- to 6-fold increase in the energy required to overcome the rotational barrier of the substituents about the indole nucleus as compared with the same dihedral angle of serotonin. This as well as the conformational restriction could increase selectivity at serotonin receptors.