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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.
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.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 1992 Oct 02; Vol. 35 (20), pp. 3625-32. - Publication Year :
- 1992
-
Abstract
- 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-]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.
- Subjects :
- Animals
Indoles pharmacology
Pyridines chemical synthesis
Pyridines pharmacology
Pyrroles chemical synthesis
Pyrroles pharmacology
Rats
Receptors, Serotonin drug effects
Receptors, Serotonin metabolism
Serotonin Receptor Agonists pharmacology
Structure-Activity Relationship
Indoles chemical synthesis
Serotonin analogs & derivatives
Serotonin Receptor Agonists chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 35
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 1433172
- Full Text :
- https://doi.org/10.1021/jm00098a005