RespireRx is developing drugs to modify neurotransmission and create advanced treatments for disorders with high unmet needs. Neurotransmission is the basic process in the brain by which specialized nerve cells called neurons communicate information with each other.

As illustrated in this figure, during neurotransmission, neurons release chemicals called neurotransmitters which attach to receptors, very specific protein structures residing on adjacent neurons. This enables neurons to communicate with one another by either increasing or decreasing the excitability of the neuron receiving the communication. For example, glutamate is the primary excitatory neurotransmitter in the brain, while gamma-amino-butyric acid (“GABA”) is the primary inhibitory neurotransmitter. Neurons also contain receptors for anandamide (AEA) and 2-arachidonoylglycerol (2-AG), the brain’s own natural cannabinoid (endocannabinoid) neurotransmitters.

The portion of the receptor at which the natural neurotransmitter attaches is known as an “orthosteric” or “agonist” binding site.  Drugs that also bind to these orthosteric sites are known as direct agonists.  Receptor protein subunit structures can vary so that the receptors can produce a variety of effects, including the flow of ions (electrically charged molecules) into the neurons or enzyme activity within the cells.  The receptors for individual neurotransmitters may vary depending upon subunit structures, altering the binding characteristics of the agonist or orthosteric site.

Certain neurotransmitter receptors are composed of protein subunits that assemble to form a pore, known as an ion channel.  For example, one type of glutamate receptor has been termed the AMPA receptor, based on the ability of AMPA, a synthetic chemical, to act as a direct agonist by binding to and activating this glutamate receptor.  The AMPA receptor is composed of four transmembrane proteins that span across the cell membrane and form a pore (see illustration below).  The binding of glutamate, or an artificial agonist such as AMPA, to its orthosteric site causes a change in the structure of the AMPA receptor by opening the ion channel and increasing the flow of positively charged ions such as sodium and calcium into the cell, resulting in an increased excitability.

In a similar fashion, one type of GABA receptor, the GABA_A receptor, is composed of five transmembrane proteins that form a pore, which when activated by GABA, opens and allows chloride to enter the neuron, thus decreasing its excitability.  The GABA_A receptor proteins are heterogeneous and form various combinations allowing for subtype specificity and neuroanatomical and pharmacological selectivIn a similar fashion, one type of GABA receptor, the GABA_A receptor, is composed of five transmembrane proteins that form a pore, which when activated by GABA, opens and allows chloride, a negatively charged ion, to enter the neuron, thus decreasing its excitability.  The GABA_A receptor proteins are heterogeneous and form various combinations allowing for subtype specificity and neuroanatomical and pharmacological selectivity.

In ResolutionRx, its pharmaceutical cannabinoid program, we are developing drugs that act as direct agonists at the CB1 and CB2 receptors for the endocannabinoid neurotransmitter systems. 

In EndeavorRx, our neuromodulator program, we are developing AMPAkines and GABAkines for the treatment of a variety of neuropsychiatric and neurological indications.