2-Substituted Tryptamines:  Agents with Selectivity for 5-HT₆Serotonin Receptors

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.

Serotonin 5-HT3 Receptor-Mediated Vomiting Occurs via the Activation of Ca2+/CaMKII-Dependent ERK1/2 Signaling in the Least Shrew (Cryptotis parva)

“…In addition, 2-Me-5-HT has affinity for 5-HT 6 Rs [38] and consequently as described above we tested the antiemetic potentials of its corresponding antagonists (Ro-046790 [39] and Ro4368554 [40]) against the induced emesis. At doses 0.25, 1, 5, 10, and 20 mg/kg (i.p.)…”

Salvinorin A: A potent naturally occurring nonnitrogenous κ opioid selective agonist

“…GF-62 cells, a stable cell line expressing the 5-HT 2A receptor (8), was used for functional studies of 5-HT 2A receptors. All other receptors were obtained as previously described (9,10) as part of the National Institute of Mental Health Psychoactive Drug Screening Program (NIMH-PDSP) resource.…”

“…Radioligand-Binding Assays. Radioligand-binding assays at human cloned GPCRs, ion channels, and transporters were performed as previously detailed (9,10) by using the resources of the NIMH-PDSP. Detailed on-line protocols are available for all assays at the NIMH-PDSP web site (http:͞͞pdsp.cwru.edu).…”

Interaction of chiral MS-245 analogs at h5-HT6 receptors

“…2 nM) as one of the first examples of a 5-HT 6 receptor antagonist. 7,8 Subsequent pharmacophoric studies have revealed that the 5-methoxy group of 1a is not required for binding (i.e., 1b; K i = 4 nM), that the benzenesulfonyl moiety can be replaced by a benzyl group (2; K i = 6 nM) with retention of antagonist action, 5 and that the indole N 1 nitrogen atom is not required for binding, as evidenced by the high affinity of, for example, isotryptamine 3 (K i = 32 nM) and indene 4 (K i = 3 nM) for this receptor population. 9 Various tryptamines lacking an N 1 substituent generally bind with reduced affinity and, like 5-hydroxytryptamine (i.e., serotonin; K i ca.…”