The abuse of psychomotor stimulants and hallucinogenic drugs that act on biogenic amine receptors is a very serious ongoing problem. The recent introduction of methylenedioxypyrovalerone (MDPV) and flakka (α-pyrrolidinopentiophenone) are glaring examples of such highly problematic drugs. We have pursued the chemical synthesis and identification of biogenic amine agonists and their antagonists as research tools and potential medications. In one example, we developed a practical nonchromatographic chemical synthesis of the 5-HT2A receptor antagonist MDL100,907 that is enabling numerous studies requiring this critical research tool. We have also studied the discriminative stimulus effects of MDL100,907 and several other drugs in order to gain further insight into their 5-HT receptor subtype(s) selectivity and the possible receptor role in certain neuropsychiatric disorders. Among the serotonin-mediated drugs, the 5-HT2A and 5-HT2C receptors are thought to be the primary sites of action. Recently, metabotropic glutamate (mGluR2) receptors have been implicated as contributors to the mechanism of hallucinogens. We assesses the role of these 5-HT and glutamate receptors as molecular targets for two tryptamine hallucinogens, N,N-dimethyltryptamine (DMT) and N,N-diisopropyltryptamine (DiPT). Drug discrimination, head twitch, and radioligand binding assays were used. A 5-HT2AR inverse agonist (MDL100907), 5-HT2CR antagonist (SB242084), and mGluR2/3 agonist (LY379268) were tested for their ability to attenuate the discriminative stimulus effects of DMT and DiPT; an mGluR2/3 antagonist (LY341495) was tested for potentiation. MDL100907 was used to attenuate head twitches induced by DMT and DiPT. Radioligand binding studies and inosital-1-phosphate (IP-1) accumulation were performed at the 5-HT2CR for DiPT. We found that MDL100907 fully blocked the discriminative stimulus effects of DMT, but only partially blocked DiPT. SB242084 partially attenuated the discriminative stimulus effects of DiPT, but produced minimal attenuation of DMT's effects. LY379268 produced potent, but only partial blockade of the discriminative stimulus effects of DMT. LY341495 facilitated DMT- and DiPT-like effects. Both compounds elicited head twitches (DiPT>DMT) which were blocked by MDL1000907. DiPT was a low-potency full agonist at 5-HT2CR in vitro. We conclude that 5-HT2AR likely plays a major role in mediating the effects of both compounds. 5-HT2C and mGluR2 receptors likely modulate the discriminative stimulus effects of both compounds to some degree.
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