The Sanford-Burnham Medical Research Institute is seeking a partner to commercialize novel positive allosteric modulators of mGluR2 for the treatment of neurological diseases and disorders.

Background
Glutamate is the most prominent neurotransmitter in the body, being present in over 50% of nervous tissue. Glutamate receptors play a role in numerous neurological, neurodegenerative, psychiatric, and psychological disorders.

Recent results of LY2140023, a potent agonist of metabotropic glutamate receptor 2/3 (mGluR2/3), developed by Eli Lilly, indicate that mGluR agonists could represent a breakthrough in the search for better antipsychotic therapies. Moreover, Merck, Johnson & Johnson, Pfizer and numerous other companies are all racing to develop mGluR-targeted drugs for schizophrenia, Alzheimer, Parkinson's disease, depression, and post-traumatic stress disorder.

The latest animal studies on physiological functions of mGluR2 elucidated its involvement in regulating the activity of the brain's reward circuitry, which plays the central role in drug addiction. The reinforcing effects of drugs involve glutamate release in the corticostriatal circuit. It was also observed that chronic drug exposure leads to a decrease in basal glutamate levels, accompanied by enhanced release of glutamate during reinstatement of drug seeking. It is postulated that medications that decrease glutamatergic transmission may reduce the reinforcing and motivational effects of drugs of abuse and alcohol and prevent drug seeking behavior leading to relapse in humans. By contrast, medication that increases glutamate release may ameliorate early drug withdrawal symptoms associated with decreased glutamatergic transmission after the cessation of chronic drug exposure.

Drug addiction is a complex medical problem manifested by a variety of behavioral and physiological disorders. A psychiatry-based addiction cycle comprises three stages: binge-intoxication, withdrawal-negative effect, and preoccupation. It is hypothesized that different components of the addiction cycle can be targeted by different medications. Medications currently on the market for the treatment of drug addiction -- by targeting dopamine and γ-aminobutyric acid neurotransmitter systems -- alleviate only some aspects related to binge-intoxication stage and the withdrawal-negative effect stage. In addition, their effectiveness is limited to a small number of abused drugs. Hence, there is an unmet medical need for novel, more efficient and more comprehensive drug-addiction treatments.

Application
Researchers at Sanford-Burnham Medical Research Institute identified and synthesized several
series of small molecules that are effective in attenuating cocaine-seeking behavior and in
alleviating various depression-like symptoms caused by the cessation of drug intake. These molecules can potentially be used as a novel method for treating various addictive disorders and also for treating neurological disorders such as senile dementia, depression, schizophrenia, Parkinson's disease, Alzheimer's disease, Huntington's chorea, pain, and epilepsy.

Technology
Metabotropic glutamate receptors 2 (mGluR2) belong to the family of G-protein coupled receptors and they are located primarily on glutamatergic afferents throughout the mammalian brain. They are inhibitory autoreceptors and they decrease excitatory glutamate transmission. They are found in several subtypes all of which exhibit amino acid homology in the ligand binding pocket.

Researchers at Sanford-Burnham Medical Research Institute developed a series of small molecule allosteric modulators of mGluR2. In one form these molecules function as mGluR2 agonists attenuating reinforcing effects of cocaine, and in the other form they function as mGluR2 antagonists which may reverse the reward deficits associated with early cocaine abstinence. While developing reliable models to study various neurological disorders is usually a precarious task, Sanford-Burnham collaborators at the University of California, San Diego (UCSD) created highly robust animal models to study the biological activity of mGluR2 modulators by following behavioral and physiological changes relevant to the treatment of drug addiction.

Advantages

·         Targeting mGluR2 is a qualitatively novel approach to treat the aspects and stages of addiction cycle which are not addressed by currently approved medications (e.g. the preoccupation stage)

·         Allosteric modulators of mGRu2 provide activity only when the endogenous agonist is present. This might provide a more normal pattern of signaling and be more attractive for long-term use

·         Subtype selective allosteric modulators of mGluR2 would likely lead to treatments with fewer side effects

·         Unlike traditional orthosteric mGlur2 agonists (LY314582 and LY379268) that cause the decrease in self-intake of both cocaine and food, allosteric agonists developed at Sanford-Burnham attenuate only the self intake of cocaine

·         These molecules show favorable pharmacokinetic properties with good bioavailability and ability to pass the blood-brain barrier

·         Analogues of these molecules could modulate the activity of mGluR receptors implicated in other neurological disorders