"A receptor is like a switch," Stuart Sealfon told BioWorld Today. "But it's not like a switch that just turns on and off - it has different on positions."
Sealfon is a professor at the Mount Sinai School of Medicine in New York. And in the Feb. 1, 2007, issue of Neuron, he and his colleagues at Mount Sinai, Columbia University and the New York State Psychiatric Institute showed that such different on positions are behind one of psychopharmacology's long-standing mysteries: why some drugs are powerful hallucinogens, while others that are nearly identical on the atomic level elicit not so much as the psychoactive equivalent of a caffeine buzz.
The idea that activation of the same receptor can lead to different intracellular consequences, depending on precisely what molecule is doing the activating, is not entirely new, Sealfon said. "But really, until this study, there's been no evidence that this is anything other than a curiosity."
The Neuron paper shows that for compounds that activate the type 2A serotonin receptor, whether they have hallucinogenic effects depends on which pathway they activate.
The team used techniques ranging from cell culture to behavioral research to determine how hallucinogens, including the gold standard LSD, and chemically closely related nonhallucinogenic compounds differed in their effects.
At the cellular level, while both hallucinogens and the nonhallucinogens they tested activated serotonin 2A receptors, the hallucinogens activated several transcription factors that were unaffected by nonhallucinogens. LSD also caused different electrophysiological responses, and activated different G protein combinations, than its nonhallucinogenic chemical cousin lisuride.
Sealfon and his colleagues also tried to determine which serotonin receptors were critical for hallucinogenic effects by testing knockouts with partially restored serotonin 2A signaling. They found that subcortical serotonin 2A receptors were not necessary for the hallucinogenic effects of psychoactive drugs. Instead, the critical receptors are most likely the ones on cortical output neurons.
Sealfon noted that the methods his team developed could allow drug discovery researchers to "get a much better handle on what gives drugs their desirable and undesirable characteristics." LSD itself, though the drug helped shape the cultural history of the 20th century, was a bust in the cold hard terms of therapeutics development. But other psychiatric drugs successfully have targeted the same receptor subtype.
As for g-protein receptor coupled drugs, they are the target of such blockbusters as Indianapolis-based Eli Lilly's Zyprexa (olanzapine,) which also targets the serotonin 2A receptor, and Kenilworth, N.J.-based Schering-Plough's Claritin (loratadine).
Biotech is in the act, too. In December, Epix Pharmaceuticals, of Lexington, Mass., signed a GPCR deal with Schering-Plough that could top $1 billion in milestone payments. (See BioWorld Today, Dec. 13, 2006.)