Structure-activity relationships of hallucinogens: Design, synthesis, and pharmacological evaluation of a series of conformationally restricted phenethylamines
Abstract
Conformationally rigidified analogs of prototypical hallucinogens were synthesized as probes for the agonist binding sites of serotonin 5-HT$\sb2$ receptors. A series of substituted tetrahydronaphthofurans was synthesized as hybrid structures of the phenethylamine and ergoline classes of hallucinogenic agents. These compounds were evaluated using in vitro radioligand competition assays for their affinity at a number of serotonin and muscarinic receptor subtypes. The syn tetrahydronaphthofuran diastereomers generally had higher affinity for the GPCRs examined than did the anti diastereomers. The compound, syn-5-Amino-9-bromo-7-methoxy-2a,3,4,5-tetrahydro-2H-naphtho (1,8-bc) furan 4, had considerable affinity for ($\sp{125}$I) DOI-labeled 5-HT$\rm\sb{2A}$ and 5-HT$\rm\sb{2c}$ cloned human receptors, with $K\sb{\rm i}$ values of 13 and 6 nM, respectively. At muscarinic receptor subtypes, 4 had $K\sb{\rm i}$ values ranging between 25-81 nM, indicating that this drug represents a novel structural class of muscarinic ligands. A series of dihydrobenzofurans and tetrahydrobenzoxepins was synthesized as rigid analogs of hallucinogenic phenethylamines in which the benzofuran and benzoxepin heterocycles were employed as conformationally restricted bioisosteres of aromatic methoxy groups. The target compounds were evaluated using in vivo behavioral assays for hallucinogen-like activity, and in vitro radioligand competition assays for their affinity at several serotonin receptor subtypes. The benzodifuran, 1-(8-Bromo-2,3,6,7-tetrahydrobenzo (1,2-b:4,5-$b\sp\prime$) difuran-4-yl)-2-aminopropane 9, was extremely potent in both pharmacological screens, having an ED$\sb{50}$ of 0.061 $\mu$mol/kg in the two-lever drug discrimination paradigm using LSD-trained rats, and a $K\sb{\rm i}$ of 18 nM at ($\sp3$H) ketanserin-labeled 5-HT$\rm\sb{2A}$ receptors. At ($\sp{125}$I) DOI-labeled human 5-HT$\rm\sb{2A}$ and 5-HT$\rm\sb{2C}$ receptors, 9 had $K{\rm\sb i}$ values of 0.48 and 0.30 nmol, respectively. The results indicate that 9 and its closely related structural analogs represent the most potent amphetamine-based hallucinogens currently available.
Degree
Ph.D.
Advisors
Nichols, Purdue University.
Subject Area
Pharmacology|Organic chemistry|Pharmacology
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