Since the classical hallucinogens were initially reported to produce their behavioral effects via a 5-HT2 agonist mechanism (i.e., the 5-HT2 hypothesis of hallucinogen action), 5-HT2 receptors have been demonstrated to represent a family of receptors that consists of three distinct subpopulations: 5-HT2A, 5-HT2B, and 5-HT2C receptors. Today, there is greater support for 5-HT2A than for 5-HT2C receptor involvement in the behavioral effects evoked by these agents. However, with the recent discovery of 5-HT2B receptors, a new question arises: do classical hallucinogens bind at 5-HT2B receptors? In the present study we examined and compared the binding of 17 phenylisopropylamines at human 5-HT2A, 5-HT2B, and 5-HT2C receptors. Although there was a notable positive correlation (r>0.9) between the affinities of the agents at all three populations of 5-HT2 receptors, structural modification resulted only in small differences in 5-HT2B receptor affinity such that the range of affinities was only about 50-fold. As with 5-HT2A and 5-HT2C receptor affinity, there is a significant correlation (r>0.9, n=8) between 5-HT2B receptor affinity and human hallucinogenic potency. Nevertheless, given that 5-HT2A and 5-HT2A/2C antagonists - antagonists with low affinity for 5-HT2B receptors - have been previously shown to block the stimulus effects of phenylisopropylamine hallucinogens, it is likely that 5-HT2A receptors play a more prominent role than 5-HT2B and 5-HT2C receptors in mediating such effects despite the affinity of these agents for all three 5-HT2 receptor subpopulations.
A major focus of our research for a number of years has been to understand the structure-activity relationship (SAR) of classical hallucinogens and their derivatives, the pharmacological action of which is believed to be mediated primarily by agonist activity at the serotonin 5-HT 2A receptor. 2,3 In particular we have sought to understand the relationship between the modes of binding of the hallucinogens containing an indole nucleus, including LSD and psilocybin, and those containing a benzene nucleus, such as mescaline and its potent structural analogue 1 (DOB). 4 In pursuing this goal, we recently reported the synthesis of the tetrahydrobenzodifuran 2 as a rigid analogue of DOB. 5 Rat behavioral data and human receptor binding data showed that 2 is more potent than 1, a finding that was consistent with a binding site model first postulated by Westkaemper and Glennon, 6 in which two hydrogenbond-donor residues in the receptor, possibly serine residues, lie on opposite sides of the molecule and form hydrogen bonds with the ether oxygen lone pairs. It was conjectured that the increase in activity of 2 relative to 1 is due to the fact that the lone pairs in 2 are fixed in an orientation favorable for forming such hydrogen bonds.It occurred to us that a protected precursor of 2 could be aromatized in one step, leading after deprotection to the fully aromatic benzodifuran 3. We anticipated that this compound would provide valuable information about the electronic requirements for binding to 5-HT 2 receptor subtypes, since sterically it would be almost identical to 2 but electronically it would differ dramatically. Thus, 3 was synthesized and evaluated in a rat behavioral assay and in binding assays using rat and cloned human 5-HT 2A receptor preparations.Chemistry. Benzodifuran 3 was prepared as depicted in Scheme 1. The aminopropane 4, available from our previous synthetic work, 5 was protected as the trifluoroacetamide 5. Bromination with Br 2 gave 6, which was then oxidized with dichlorodicyanobenzoquinone (DDQ) in toluene, yielding the aromatized derivative 7. Deprotection produced the free amine that was neutralized with ethanolic HCl and precipitated from ether as fine white crystals of the hydrochloride salt of 3. Pharmacology. Compound 3 was evaluated in the two-lever drug discrimination assay in two groups of rats, each of which was trained to discriminate the effects of ip injections of saline from those of either LSD or DOI; the methods have been described previously. 5 Potencies were calculated as ED 50 values with 95% confidence intervals. 7 In addition, 3 was assayed for its ability to displace the highly selective 5-HT 2A antagonist [ 3 H]MDL 100,907 8 from rat prefrontal cortex and to compete for the nonselective 5-HT 2 agonist [ 125 I]DOI at cloned human 5-HT 2A and 5-HT 2C receptors and for [ 3 H]-serotonin at cloned human 5-HT 2B receptors; the methods employed here have also been described previously. 5Results and Discussion. Compound 3 possessed a K i of 0.23 ( 0.03 nM in competition with the 5-...
Allosteric potentiators amplify the sensitivity of physiologic control circuits, a mode of action that could provide therapeutic advantages. This hypothesis was tested with the dopamine D1 receptor potentiator DETQ [2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one]. In human embryonic kidney 293 (HEK293) cells expressing the human D1 receptor, DETQ induced a 21-fold leftward shift in the cAMP response to dopamine, with a Kb of 26 nM. The maximum response to DETQ alone was ∼12% of the maximum response to dopamine, suggesting weak allosteric agonist activity. DETQ was ∼30-fold less potent at rat and mouse D1 receptors and was inactive at the human D5 receptor. To enable studies in rodents, an hD1 knock-in mouse was generated. DETQ (3–20 mg/kg orally) caused a robust (∼10-fold) increase in locomotor activity (LMA) in habituated hD1 mice but was inactive in wild-type mice. The LMA response to DETQ was blocked by the D1 antagonist SCH39166 and was dependent on endogenous dopamine. LMA reached a plateau at higher doses (30–240 mg/kg) even though free brain levels of DETQ continued to increase over the entire dose range. In contrast, the D1 agonists SKF 82958, A-77636, and dihydrexidine showed bell-shaped dose-response curves with a profound reduction in LMA at higher doses; video-tracking confirmed that the reduction in LMA caused by SKF 82958 was due to competing stereotyped behaviors. When dosed daily for 4 days, DETQ continued to elicit an increase in LMA, whereas the D1 agonist A-77636 showed complete tachyphylaxis by day 2. These results confirm that allosteric potentiators may have advantages compared with direct-acting agonists.
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