Journal of Medicinal Chemistry
September 21, 2006
Thomas H. Mclean, Jason C. Parrish, Michael R Braden et al.
115 citations
A series of rigid analogues of the hallucinogenic phenethylamine 2C-B was synthesized to determine the active shape these molecules adopt when binding to the 5-HT(2A) receptor. Computer docking predicted that one benzocyclobutene analogue, (R)-2, would be the most potent. Chemical resolution and X-ray crystallography confirmed this: (R)-2 was equipotent to LSD in rats trained to discriminate LSD from saline, making it one of the most potent and selective compounds yet tested in this assay. The compound also acted as a functionally selective agonist at the 5-HT(2A) receptor, showing 65-fold greater potency in stimulating phosphoinositide turnover than in producing arachidonic acid release. If hallucinogenic effects are linked to arachidonic acid production, such selective agonists might lack the intoxicating properties of LSD.
Journal of Neurochemistry
August 15, 2006
Jason C. Parrish, David E. Nichols
61 citations
Activation of the serotonin 5-HT(2A) receptor stimulates the production and release of the endocannabinoid 2-arachidonoylglycerol. In cells expressing the rat 5-HT(2A) receptor, stimulation with 10 μM serotonin led to formation and release of 2-arachidonoylglycerol, partially dependent on phosphatidylinositol-specific phospholipase C activation. Diacylglycerol from phospholipase D or phosphatidylcholine-specific phospholipase C did not contribute. The findings support a model where neurotransmitters like serotonin regulate endocannabinoid tone at excitatory synapses via phospholipase C-coupled G-protein coupled receptors.
Journal of Neurochemistry
November 8, 2005
Jason C. Parrish, M. Braden, Emily Gundy et al.
40 citations
Phenylisopropylamine hallucinogens (such as DOI) produce a stronger activation of the serotonin 5-HT2A receptor than their phenethylamine counterparts (such as mescaline), as measured by the receptor's ability to trigger phosphatidyl inositol hydrolysis in cells. Among phenylisopropylamines, those with the (R) configuration at the alpha carbon are more potent than those with the (S) configuration. Computer simulations of how these molecules dock into the receptor reveal different orientations of key binding site residues. The findings support the idea that phenylisopropylamines' greater hallucinogenic potency stems from higher intrinsic activity at the 5-HT2A receptor, though the three-dimensional structure of receptor microdomains also matters.
Journal of Medicinal Chemistry
July 1, 2003
James J. Chambers, Jason C. Parrish, Niels Jensen et al.
27 citations
Conformationally constrained tetrahydronaphthofurans were designed to study the optimal shape of the 2-aminoethyl moiety in phenethylamine-type serotonin 5-HT(2A) receptor agonists. In vitro assays showed that benzofuran-containing analogues (6a and 6b) had significantly higher affinity for 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors than benzodihydrofuran-containing compounds. The most potent compound, 6b, had K(i) values of 2.6 nM at 5-HT(2A) and 1.1 nM at 5-HT(2C) cloned rat receptors. Despite high affinity, these naphthofuran compounds lacked high intrinsic activity at the 5-HT(2A) receptor in the phosphoinositide hydrolysis assay. Compound 6b failed to substitute for LSD in a rat drug discrimination assay, typical for low intrinsic activity compounds. Conformational constraint produced high-affinity partial agonists, but full receptor activation requirements remain unidentified.
Journal of Medicinal Chemistry
June 21, 2006
Thomas H. Mclean, James J. Chambers, Jason C. Parrish et al.
24 citations
A new molecule, C-(4,5,6-trimethoxyindan-1-yl)-methanamine, was designed based on a computer model of the 5-HT(2A) receptor. This compound showed three times higher affinity and potency than mescaline at the receptor, with equal efficacy. In drug discrimination tests, it fully substituted for LSD and was five times more potent than mescaline. Separating the molecule into its mirror-image forms confirmed the computer predictions: the R-(+) isomer had higher affinity and potency than the S-(-) isomer, with efficacy similar to mescaline at the 5-HT(2A) receptor.