Benzofuran bioisosteres of hallucinogenic tryptamines.
The benzofuran analogues of the hallucinogens 5-methoxy-N,N-dimethyltryptamine and 5-methoxy-alpha-methyltryptamine were synthesized and evaluated for affinity at the serotonin 5-HT2 and 5-HT1A receptors in rat brain homogenate, labeled with [125I]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ([125I]DOI) and [3H]-8-hydroxy-2-(N,N-di-n-propylamino)tetralin ([3H]-8-OH-DPAT), respectively. At the 5-HT2 receptor, the benzofurans had slightly decreased affinities, approximately one-third and one-sixth those of the indoles, for the primary amines and the tertiary amines, respectively. The benzofurans also had lower affinity at the 5-HT1A receptor, but decreased only about 20-30% from that of the indole isosteres. Thus, the 5-HT1A receptor is less discriminating with respect to preference for an indole versus a benzofuran, although all of the compounds did have higher affinities for the 5-HT2 receptor than for the 5-HT1A receptor. It is suggested that benzofurans may be useful in the design of serotonin receptor ligands.
Tomaszewski
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Department of Medicinal Chemistry, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907.
Johnson
M P
MP
Huang
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Nichols
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DE
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000662:Amphetamines / Q000378:metabolism; D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000378:metabolism; D005021:Ethylamines / Q000138:chemical synthesis* / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D006213:Hallucinogens / Q000138:chemical synthesis* / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000378:metabolism; D014363:Tryptamines / Q000138:chemical synthesis* / Q000378:metabolism
D000662:Amphetamines; D001572:Benzofurans; D005021:Ethylamines; D006213:Hallucinogens; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013764:Tetrahydronaphthalenes; D014363:Tryptamines; C074917:N,N-dimethyl-2-(5-methoxybenzofuran-3-yl)ethanamine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine