C-(4,5,6-trimethoxyindan-1-yl)methanamine: a mescaline analogue designed using a homology model of the 5-HT2A receptor.

A conformationally restricted analogue of mescaline, C-(4,5,6-trimethoxyindan-1-yl)-methanamine, was designed using a 5-HT(2A) receptor homology model. The compound possessed 3-fold higher affinity and potency than and efficacy equal to that of mescaline at the 5-HT(2A) receptor. The new analogue substituted fully for LSD in drug discrimination studies and was 5-fold more potent than mescaline.

A complex signaling cascade links the serotonin2A receptor to phospholipase A2 activation: the involvement of MAP kinases.

Previous studies in our laboratory have shown that in NIH3T3-5HT2A cells, 5-HT-induced AA release is PLA2-coupled and independent of 5-HT2A receptor-mediated PLC activation. Although 5-HT2A receptor-mediated PLC activation is known to be Galphaq-coupled, much less is understood about 5-HT2A receptor-mediated PLA2 activation. Therefore, the studies presented here were aimed at elucidating the signal transduction pathway linking stimulation of the 5-HT2A receptor to PLA2 activation.

Synthesis and pharmacological characterization of a series of geometrically constrained 5-HT(2A/2C) receptor ligands.

In studies of the SAR of phenethylamine-type serotonin 5-HT(2A) receptor agonists, substituted conformationally constrained tetrahydronaphthofurans were designed to investigate the optimal conformation of the 2-aminoethyl moiety. These compounds were tested using in vitro assays for affinity at 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors. The benzofuran-containing analogues, 6a and 6b, had significantly higher affinity for the 5-HT receptors tested than did the benzodihydrofuran-containing compounds, 4a, 4b, 5a, and 5b.

Serotonin 5-hydroxytryptamine 2A receptor-coupled phospholipase C and phospholipase A2 signaling pathways have different receptor reserves.

NIH3T3 cells stably expressing the rat 5-hydroxytryptamine 2A (5-HT 2A) receptor (5500 fmol/mg) were used to explore further the capacity of structurally distinct ligands to elicit differential signaling through the phospholipase C (PLC) or phospholipase A 2 (PLA 2) signal transduction pathways. Initial experiments were designed to verify that 5-HT 2A receptor-mediated PLA 2 activation in NIH3T3 cells is independent from, and not a subsequent result of, 5-HT 2A receptor-mediated PLC activation. In addition, we also explored the extent of receptor reserve for the endogenous ligand, 5-HT, for both PLC and PLA 2 activation.

Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine1A receptor-mediated behavioral effects overlap its other properties in rats.

Rationale: There is substantial evidence that lisuride can produce effects linked to 5-HT(1A) receptor occupancy. Nevertheless, this action has generally been ignored in the mechanism of action of lisuride, in favor of an exclusive role for dopamine receptors in considering its antiparkinsonian effects, or an exclusive role of 5-HT(2A/2C) receptor activation in hallucinogenesis. These conclusions are surprising when one considers that the potent interaction of lisuride with 5-HT(1A) receptors has been demonstrated in several different laboratories and that activation of 5-HT(1A) and 5-HT(1B) receptors can modulate dopaminergically mediated responses.