2-Substituted tryptamines: agents with selectivity for 5-HT(6) serotonin receptors.
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Glennon RA, Lee M, Rangisetty JB, Dukat M, Roth BL, Savage JE, McBride A, Rauser L, Hufeisen S, Lee DK
2-Substituted tryptamines: agents with selectivity for 5-HT(6) serotonin receptors.
J Med Chem. 2000 Mar 9;43(5):1011-8.
- PubMed ID
- 10715164 [ View in PubMed]
- Abstract
Several 2-alkyl-5-methoxytryptamine analogues were designed and prepared as potential 5-HT(6) serotonin agonists. It was found that 5-HT(6) receptors accommodate small alkyl substituents at the indole 2-position and that the resulting compounds can bind with affinities comparable to that of serotonin. In particular, 2-ethyl-5-methoxy-N, N-dimethyltryptamine (8) binds with high affinity at human 5-HT(6) receptors (K(i) = 16 nM) relative to 5-HT (K(i) = 75 nM) and was a full agonist, at least as potent (8: K(act) = 3.6 nM) as serotonin (K(act) = 5.0 nM), in activating adenylate cyclase. Compound 8 displays modest affinity for several other populations of 5-HT receptors, notably h5-HT(1A) (K(i) = 170 nM), h5-HT(1D) (K(i) = 290 nM), and h5-HT(7) (K(i) = 300 nM) receptors, but is otherwise quite selective. Compound 8 represents the first and most selective 5-HT(6) agonist reported to date. Replacing the 2-ethyl substituent with a phenyl group results in a compound that retains 5-HT(6) receptor affinity (i.e., 10: K(i) = 20 nM) but lacks agonist character. 2-Substituted tryptamines, then, might allow entry to a novel class of 5-HT(6) agonists and antagonists.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Dimethyltryptamine 5-hydroxytryptamine receptor 6 Protein Humans YesNot Available Details - Binding Properties
Drug Target Property Measurement pH Temperature (°C) Clozapine 5-hydroxytryptamine receptor 6 Ki (nM) 10 N/A N/A Details Clozapine 5-hydroxytryptamine receptor 7 Ki (nM) 9 N/A N/A Details Ergotamine 5-hydroxytryptamine receptor 1D Ki (nM) 0.8 N/A N/A Details Fluoxetine Sodium-dependent serotonin transporter Ki (nM) 3.5 N/A N/A Details Nortriptyline Sodium-dependent noradrenaline transporter Ki (nM) 6.3 N/A N/A Details