Synthesis and pharmacological evaluation of fluorinated hallucinogenic tryptamine analogs and thienopyrrole bioisosteres of N,N-dimethyltryptamine
Abstract
A series of fluorinated tryptamine analogs of the hallucinogenic compounds DMT, DET, Psilocin, and 5-methoxy-DMT was synthesized to investigate why 6-fluoro-DET is inactive as a hallucinogen, and to determine the effects of fluorination in the molecular recognition of these compounds at serotonin receptor subtypes. The target compounds were evaluated using in vivo behavioral assays for hallucinogen-like and 5-HT$\sb{\rm 1A}$ activity, and in-vitro radioligand competition assays for their affinity at 5-HT$\sb{\rm 1A}$ receptor sites. Hallucinogen-like activity, evaluated in the two-lever drug discrimination paradigm using LSD-trained rats, was attenuated or abolished for all of the fluorinated analogs. The tryptamine, 4-fluoro-5-methoxy-DMT 1, displayed high 5-HT$\sb{\rm 1A}$ activity in both assays, with potencies comparable to the standard 5-HT$\sb{\rm 1A}$ full agonist 8-OH-DPAT. The ED$\sb{50}$ of 1 in the two-lever drug discrimination paradigm using LY293284-trained rats was 0.17 $\mu$mol/kg, and the K$\sb{\rm i}$ at ($\sp3$H) -8-OH-DPAT-labeled 5-HT$\sb{\rm 1A}$ receptors was 3.8 nM. The results indicate that fluorination of hallucinogenic tryptamines generally attenuates 5-HT$\sb2$ and 5-HT$\sb{\rm 1A}$ receptor affinity, with the notable exception of 4-fluoro-5-methoxy substitution, which may involve a novel mechanism in the molecular recognition of tryptamines at serotonin receptors. The hypothetical formation of a hydrogen bond involving the 4-fluoro substituent in the 5-HT$\sb{\rm 1A}$ receptor pocket is discussed. The thienoypyrrole positional isomers 6- (2-(N,N-dimethylamino)ethyl) -4H-thieno (3,2-b) pyrrole 2 and 4- (2-(N,N-dimethylamino)ethyl) -6H-thieno (2,3-b) pyrrole 3 were synthesized as bioisosteres of DMT.
Degree
Ph.D.
Advisors
Nichols, Purdue University.
Subject Area
Pharmacology|Organic chemistry|Neurology
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