1-(2-Aminoethyl)-3-methyl-8,9-dihydropyrano[3,2-e]indole: A rotationally restricted phenolic analog of the neurotransmitter serotonin and agonist selective for serotonin (5-HT2-type) receptors

Article abstract of DOI:10.1021/jm00098a005

A series of rotationally restricted phenolic analogs of the neurotransmitter serotonin has been synthesized with the 5-hydroxyindole portion of serotonin replaced by a dihydropyrano[3,2-e]indole (1, 3, 4, and 5) and a dihydropyrano[2,3-f]indole (2). The receptor binding profile of these compounds has been studied and compared to the natural substrate serotonin. The dihydropyrano[3,2-e]indole derivatives (1, 3, 4, and 5) possess lower affinity for 5-HT₁ receptors but equal or greater affinity for 5-HT₂ receptors. Like serotonin, these compounds dose-dependently stimulated phosphatidylinositol turnover in rat brain slices. Moreover, the response to 1-(2-aminoethyl)-3-methyl-8,9-dihydropyrano[3,2-e]indole (5, CP-132,484) and 1-(2-aminoethyl)-8,9-dihydropyrano[3,2-e]indole (4) is selectively antagonized by 5-HT₂ receptor antagonists establishing these tryptamines as selective 5-HT₂ receptor agonists. The high affinity and potency of 5 for 5- HT₂ receptors suggests that the C5-hydroxy group in serotonin can function as a hydrogen bond acceptor in a 5-HT₂ receptor with a directionality of interaction which is down and away from C6 in serotonin (Figure 5). Furthermore, the potent affinity of these compounds for 5-HT₂ receptors coupled with their poor affinity for 5-HT₁ receptors indicates that the aminoethyl side chain of serotonin adopts significantly different conformations in 5-HT₁ versus 5-HT₂ receptors.