Publications by authors named "S P Frescas"

A strategy to replace the ethylamine side chain of 2,5-dimethoxy-4-iodoamphetamine (DOI, 1a), and 2,5-dimethoxy-4-bromoamphetamine (DOB, 1b) with a cyclopropylamine moiety was successful in leading to compounds with high affinity at the 5-HT(2) family of receptors; and the more potent stereoisomer of the cyclopropane analogues had the expected (-)-(1R,2S)-configuration. Screening for affinity at various serotonin receptor subtypes, however, revealed that the cyclopropane congeners also had increased affinity at several sites in addition to the 5-HT(2A) and 5-HT(2B) receptors. Therefore, at appropriate doses - although (-)-4 and (-)-5 may be useful as tools to probe 5-HT(2) receptor function - one would need to be mindful that their selectivity for 5-HT(2A) receptors is somewhat less than for DOI itself.

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The title compound ([3H]INBMeO) was prepared by an O,O-dimethylation reaction of a t-BOC protected diphenolic precursor using no carrier added tritiated iodomethane in DMF with K(2)CO(3). Removal of the t-BOC protecting group and purification by HPLC afforded an overall yield of 43%, with a radiochemical purity of 99% and specific activity of 164Ci/mmol. The new radioligand was suitable for labeling human 5-HT(2A) receptors in two heterologous cell lines and had about 20-fold higher affinity than [(3)H]ketanserin.

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Lysergic acid amides were prepared from (R,R)-(-)-, (S,S)-(+)-, and cis-2,4-dimethyl azetidine. The dimethylazetidine moiety is considered here to be a rigid analogue of diethylamine, and thus, the target compounds are all conformationally constrained analogues of the potent hallucinogenic agent, N,N-diethyllysergamide, LSD-25. Pharmacological evaluation showed that (S,S)-(+)-2,4-dimethylazetidine gave a lysergamide with the highest LSD-like behavioral activity in the rat two lever drug discrimination model that was slightly more potent than LSD itself.

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N-Ethyl-5-trifluoromethyl-2-aminoindan (ETAI) and 5-trifluoromethyl-2-aminoindan (TAI) were synthesized to examine the effects of side-chain cyclization on the pharmacology of the anorectic drugs fenfluramine (FEN) and norfenfluramine (norFEN), respectively. ETAI and TAI inhibited synaptosomal accumulation of 5-HT but were less effective at inhibiting catecholamine uptake than FEN or norFEN, respectively. In vivo, ETAI and TAI were less neurotoxic than FEN or norFEN; decreases in the number of [3H]paroxetine-labeled 5-HT uptake sites were 50% less than the decreases produced by FEN or norFEN.

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A method was found to synthesize 1-(2,5-dimethoxy-4-(trifluoromethyl) phenyl)-2-aminopropane, 5, and its des-alpha-methyl congener 2-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)aminoethane, 6, the trifluoromethyl analogs of substituted hallucinogenic phenethylamine derivatives such as 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (3, DOI) that are potent 5-HT2A/2C agonists. In our hands, 5 and 6 have proven to have affinity for [3H]ketanserin or [125I]-3-labeled 5-HT2A/2C sites in rat cortex comparable to or higher than the analogous bromo or iodo analogs. Similarly, 5 and 6 had potency comparable to or slightly greater than that of their bromo or iodo congeners in the two-lever drug discrimination assay in rats trained to discriminate saline from LSD tartrate.

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