Functional selectivity can be exploited to learn more about marketed drugs and reveal unique actions that can guide the development of next-generation therapies. All clinically effective antipsychotics interact with the D2 class of dopamine receptors (D2R), and their physiological effects are mediated through GPCR or beta-arrestin signaling pathways.
Bernard Masri, Ph.D., of Duke University Medical Center, tested several antipsychotics including halperidol, clozapine, and risperidone. He found that they share a common molecular mechanism involving inhibition of D2R/beta-arrestin signaling, yet they show highly diverse effects on D2R/G protein signaling. Selective targeting of D2R/beta-arrestin signaling pathways may lead to better antipsychotic drugs.
Vince Setola, Ph.D., a research assistant professor in Dr. Roth’s laboratory, presented unpublished data revealed for the first time at the meeting. While screening drug libraries to find drugs that activate the serotonin 5-HT2B receptor, Dr. Setola stumbled on an example of functional selectivity with likely clinical relevance.
Dr. Roth’s team previously showed that drugs known to cause valvular heart disease such as fenfluramine for weight loss and pergolide for Parkinson’s disease activate 5-HT2B receptors. These drugs also cause hyperproliferation of plaques in heart tissue that lead to valve dysfunction.
Dr. Setola theorized that screening drug compounds for agonists of 5-HT2B might predict those at risk for causing valvular heart disease. He screened 2,500 compounds in libraries of commercial and investigational drugs and found several with clearcut 5-HT2B activity.
Surprisingly, some are drugs prescribed today such as ropinirole for restless leg syndrome, guafacine for hypertension, oxymetazoline in over-the-counter decongestants, and quinidine for antirhythmia. None were previously known to act through 5-HT2B receptors, and none have yet to be associated with valvular heart disease. The greatest diversity in their functional selectivity was revealed in the heart-cell proliferation assays, rather than in standard tests of receptor activity such as calcium flux or inositol triphosphate accumulation. “When screening compounds to look for functional activity, it’s a good idea to use physiologically relevant screens,” Dr. Setola said.
Other speakers agreed that assays must be optimized to detect allosteric modulation and functional selectivity, since drug efficacy and potency are assay dependent. In vitro assays must be designed to pick up subtleties and interactions that are cell-type dependent. In addition to in vitro assays, better preclinical animal models are needed to measure, for instance, the negative and cognitive symptoms associated with schizophrenia. “Assay design is the key,” said Roth.
Invitrogen already supplies researchers with assays to measure GPCR receptor activity such as Tango cell-based assays and GeneBLAzer™. “Our assays meet some needs of these researchers, but we will be developing new ones based on what the researchers are describing here,” said Mark Keck, director of marketing with Invitrogen Discovery Sciences.
“In 1991, one-third of drugs failed due to lack of efficacy, and it’s amazing that one-third of drugs still fail today,” said Arthur Christopoulos, co-director of the drug discovery biology laboratory at Monash University. A deeper understanding of allosteric modulation and functional selectivity could improve the design of new clinical compounds that act through GCPRs. Researchers are just starting to tackle this new frontier. Exactly how they will harness the emerging knowledge about allosteric modulation and functional selectivity to create better drugs remains to be seen.