DIHYDROBENZOFURAN ANALOGS OF HALLUCINOGENS .4. MESCALINE DERIVATIVES

Dihydrobenzofuran and tetrahydrobenzodifuran functionalities were empl oyed as conformationally restricted bioisosteres of the aromatic metho xy groups in the prototypical hallucinogen, mescaline (1). Thus, (2-am inoethyl)-6,7-dimethoxy-2,3-dihydrobenzofuran hydrochloride (8) and yd robenzo[1,2-b:5,4-b']difuran-4-yl)-2-amimoethane hydrochloride (9) wer e prepared and evaluated along with 1 for activity in the two-lever dr ug discrimination (DD) paradigm in rats trained to discriminate saline from LSD tartrate (0.08 mg/kg). Also, 1, 8, and 9 were assayed for th eir ability to displace [H-3]ketanserin from rat cortical homogenate 5 -HT2A receptors and [H-3]8-OH-DPAT from rat hippocampal homogenate 5-H T1A receptors. In addition, these compounds were evaluated for their a bility to compete for agonist and antagonist binding to cells expressi ng cloned human 5-HT2A, 5-HT2B, and 5-HT2C receptors. Finally, agonist efficacy was assessed by measurement of phosphoinositide hydrolysis i n NIH 3T3 cells expressing the rat 5-HT2A or 5-HT2C receptors. Althoug h 1 fully substituted for LSD in the DD assays (ED50 = 33.5 mu mol/kg) , neither 8 nor 9 substituted for LSD, with just 50% of the rats, admi nistered 8 selecting the drug lever, and only 29% of the rats administ ered 9 selecting the drug lever. All of the test compounds had micromo lar affinity for the 5-HT1A and 5-HT2A receptors in rat brain homogena te. Curiously, the rank order of affinities of the compounds at 5-HT2A sites was opposite their order of potency in the behavioral assay. An evaluation for ability to stimulate phosphoinositide turnover as a me asure of functional efficacy revealed that all the compounds were of a pproximately equal efficacy to serotonin in 5-HT2C receptors. At 5-HT2 A receptors, however, 8 and 9 were significantly less efficacious, eli citing only 61 and 45%, respectively, of the maximal response. These r esults are consistent with the proposed mechanism of action for phenet hylamine hallucinogens, that such-compounds must be full agonists at t he 5-HT2A receptor subtype. In contrast to the 2,5-dimethoxy-substitut ed phenethylamines, where rigidification of the methoxy groups had no deleterious effect on activity, the loss of activity in the 3,4,5-trio xygenated mescaline analogues may suggest that the 3 and 5 methoxy gro ups must remain conformationally mobile to enable-receptor activation.