A Novel (Benzodifuranyl)aminoalkane with Extremely Potent Activity at the 5-HT_2A Receptor

Abstract

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-...

‘Hybrid’ benzofuran–benzopyran congeners as rigid analogs of hallucinogenic phenethylamines

“…9 In a prior study, we also had shown that expansion of both furan rings to the larger, six-membered pyrans led to a nearly ten-fold loss of affinity and in vivo behavioral activity, although compounds 3 were still significantly more potent than the flexible prototype 1. 7 In this report, new compounds 4-6 further support those earlier observations and confirm the proper orientation of the arene oxygen lone pair electrons for optimal activity at the 5-HT 2A receptor.…”

“…Aromatization of the furan ring of 4b was accomplished using a method analogous to that employed by Parker, et al 9 As shown in Scheme 3, dihydrofuran 17b was protected as its Ntrifluoroacetamide 19, brominated to provide 20, and then oxidized using 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) to afford the protected intermediate 21. Deprotection in strong base gave 6, the final target molecule.…”

3D-QSAR study of hallucinogenic phenylalkylamines by using CoMFA approach

“…To validate the established model, two separately synthesized potential hallucinogenic compounds [20] ( Figure 6) were used for prediction. The predicted values suggest that compound 2 have higher activity than compound 1.…”

Delayed onset of seizures and toxicity associated with recreational use of Bromo-dragonFLY

“…The chemical structure of Bromo-dragonFLY is shown in comparison with serotonin in Figure 1. These compounds have been developed as potent research tools for investigation of the serotonin receptor family, in particular the 5-HT2 subfamily of receptors [7][8][9][10]. These agents were thought to have a potential role in the development of novel antidepressant drugs that stimulate release of serotonin, differing from conventional antidepressants that inhibit the reuptake of serotonin.…”