Development Of Novel Muscle Relaxant Compounds

Purpose: Generation of a more potent muscle relaxant compound, with less abuse potential. Materials and Methods: Whole cell patch clamp electrophysiology technique, HEK-t stable cell line expressing H-α1β2γ2s, H-α2β2γ2s and R- α3β2γ2s, cell culture, gravity based rapid drug application system, drug synthesis via a matrix approach. Summary: The carbamate derivative carisoprodol (trade name Soma) is a widely prescribed skeletal muscle relaxant. Its recreational use is an increasing problem. Consequences of abuse include withdrawal symptoms, delusions, seizures and even death. Consequently, in 2012 carisoprodol was classified at the federal level as a schedule IV controlled substance. Its primary metabolite, meprobamate is also a controlled substance, and there remains a pressing need for efficacious muscle relaxants with reduced potential for abuse. Both carisoprodol and meprobamate act on GABAA receptors, the predominant inhibitory neurotransmitter receptor in the central nervous system, in a subunit-dependent manner. Work in recent years has shown that receptors expressing the α1 subunit are associated with anticonvulsive, sedative, and anxiolytic properties, whereas those expressing α2 and α3 subunits are associated with muscle relaxant properties. Here, using whole cell patch clamp electrophysiology, we are assessing the α subunit-related allosteric modulatory and direct gating effects of a series of compounds prepared via a matrix approach and surveying different alkyl substituents at the two positions of the carisoprodol molecule, with the goal of identification of a molecule likely to be efficacious for muscle relaxation, but with a reduced abuse potential profile. Conclusions: Studies to date indicate structural differences at the two positions of the carisoprodol molecule lead to differences in the allosteric modulatory and direct gating effects of the ligands on GABAA receptors. Subsequent testing in animal models will help to identify lead molecules for further development. As the GABAA receptor is a target for several therapeutic classes of drugs, other indications are also possible.