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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
- Source :
- Journal of Medicinal Chemistry. 35:3625-3632
- Publication Year :
- 1992
- Publisher :
- American Chemical Society (ACS), 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 :
- Agonist
Serotonin
Indoles
Pyridines
medicine.drug_class
Stereochemistry
Structure-Activity Relationship
chemistry.chemical_compound
Drug Discovery
medicine
Animals
Structure–activity relationship
Pyrroles
heterocyclic compounds
Neurotransmitter
Receptor
5-HT receptor
Indole test
organic chemicals
Rats
Serotonin Receptor Agonists
chemistry
Receptors, Serotonin
Molecular Medicine
Endogenous agonist
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 35
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....377aca7b9b2547dc65414bc8d3892157