Dihydrobenzofuran and tetrahydrobenzodifuran functionalities were employed as conformationally restricted bioisosteres of the aromatic methoxy groups in the prototypical hallucinogen, mescaline (1). Thus, 4-(2-aminoethyl)-6,7-dimethoxy-2,3-dihydrobenzofuran hydrochloride and 1-(8-methoxy-2,3,5,6-tetrahydrobenzo[1,2-b:5,4-b′]difuran-4-yl)-2-aminoethane hydrochloride (9) were prepared and evaluated along with 1 for activity in the two-lever drug discrimination (DD) paradigm in rats trained to discriminate saline from LSD tartrate (0.08 mg/kg). Also, 1, 8, and 9 were assayed for their ability to displace [ 3 H]ketanserin from rat cortical homogenate 5-HT 2A receptors and [ 3 H]8-OH-DPAT from rat hippocampal homogenate 5-HT 1A receptors. In addition, these compounds were evaluated for their ability to compete for agonist and antagonist binding to cells expressing cloned human 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors. Finally, agonist efficacy was assessed by measurement of phosphoinositide hydrolysis in NIH 3T3 cells expressing the rat 5-HT 2A or 5-HT 2C receptors. Although 1 fully substituted for LSD in the DD assays (ED 50 ) 33.5 µmol/kg), neither 8 nor 9 substituted for LSD, with just 50% of the rats administered 8 selecting the drug lever, and only 29% of the rats administered 9 selecting the drug lever. All of the test compounds had micromolar affinity for the 5-HT 1A and 5-HT 2A receptors in rat brain homogenate. Curiously, the rank order of affinities of the compounds at 5-HT 2A sites was opposite their order of potency in the behavioral assay. An evaluation for ability to stimulate phosphoinositide turnover as a measure of functional efficacy revealed that all the compounds were of approximately equal efficacy to serotonin in 5-HT 2C receptors. At 5-HT 2A receptors, however, 8 and 9 were significantly less efficacious, eliciting only 61 and 45%, respectively, of the maximal response. These results are consistent with the proposed mechanism of action for phenethylamine hallucinogens, that such compounds must be full agonists at the 5-HT 2A receptor subtype. In contrast to the 2,5-dimethoxysubstituted phenethylamines, where rigidification of the methoxy groups had no deleterious effect on activity, the loss of activity in the 3,4,5-trioxygenated mescaline analogues may suggest that the 3 and 5 methoxy groups must remain conformationally mobile to enable receptor activation.

An Improved synthesis of il potent serotonin agonist la and its novel derivattve lb is deacrthed. makmg use of a Clalsen rearrangement whose unstable phenolic product IS methylated and isomertred in situ. This method may he of general use in the synthesis of o-methoxylated phenethylamine dertvatives. The synthesis nlso includes an unusutl, one pot dcmethylattonlprtmary alcohol hrommation wth boron trihromide. Copyright 0 1996 Elsevier Science Ltd

famously argued that there is a link between capitalism and freedom. "A society which is socialist," he wrote in Capitalism and Freedom, "cannot also be democratic, in the sense of guaranteeing individual freedom. " As an empirical ma er, that statement remains as roughly true now as Friedman's related claim that there is "no example in time or place of a society that has been marked by a large measure of political freedom, and that has not also used something comparable to a free market to organize the bulk of economic activity. " A socialist might quibble that the assertion is cra ed to elide very stark distinctions between societies, hiding some important dimensions in which politically free Sweden, for example, diverges in economic policy from the laissez-faire Anglo-sphere. But even in the social-democratic Nordics, much of economic life, the "bulk" perhaps, plays out through money-intermediated arrangements between nonstate actors.

Dihydrobenzofuran and tetrahydrobenzodifuran functionalities were employed as conforma-tionally restricted bioisosteres of the aromatic methoxy groups in the prototypical hallucinogen, mescaline (1). Thus, 4-(2-aminoethyl)-6,7-dimethoxy-2,3-dihydrobenzofuran hydrochloride (8) and 1-(8-methoxy-2,3,5,6-tetrahydrobenzo[1,2-b:5,4-b′]difuran-4-yl)-2-aminoethane hydrochlo-ride (9) were prepared and evaluated along with 1 for activity in the two-lever drug discrimination (DD) paradigm in rats trained to discriminate saline from LSD tartrate (0.08 mg/kg). Also, 1, 8, and 9 were assayed for their ability to displace [3H]ketanserin from rat cortical homogenate 5-HT2A receptors and [3H]8-OH-DPAT from rat hippocampal homogenate 5-HT1A receptors. In addition, these compounds were evaluated for their ability to compete for agonist and antagonist binding to cells expressing cloned human 5-HT2A, 5-HT2B, and 5-HT2C receptors. Finally, agonist efficacy was assessed by measurement of phosphoinositide ...

Abstract: An Improved synthesis of il potent serotonin agonist la and its novel derivattve lb is deacrthed. makmg use of a Clalsen rearrangement whose unstable phenolic product IS methylated and isomertred in situ. This method may he of general use in the synthesis of o-methoxylated phenethylamine dertvatives. The synthesis nlso includes an unusutl, one pot dcmethylattonlprtmary alcohol hrommation wth boron trihromide. Copyright 0 1996 Elsevier Science Ltd Working to improve the synthesis of la (a potent 5-HT2 agonist which had been synthesized previously in our laboratory ’), we have found a reaction that may be of general use in the synthesis of n-methoxylated amphetamines, many of which are known to have agonist activity at central 5-HTZAIzC receptors.2 This approach successfully yielded la, as well as lb, a novel iodo derivative. H&O la, X = Br lb,X=l In the original sequence, rearrangement of the nonbrominated congener of 6 had given a predominance of the undesired 6-ally1 prod...