Therapeutic Targets:

Migraines

Protease-Activated Receptor-2 (PAR-2)

Migraine pain is a disabling condition that affects over 36 million people in the US, particularly women between 18 and 55 years of age, and are responsible for decreased work productivity, absenteeism, and a reduced quality of life for the sufferer.

How do Migraines happen?

Migraines can be triggered by many environmental factors, such as hormonal fluctuations, sensory stimuli, food additives, exertion or sleep deprivation, resulting in an imbalance of signals from the hypothalamus. This leads to activation of pain sensing neurons, called nociceptors that innervate the head and face and release of neurotransmitters, that mediate a series of events that we typically associate with inflammation, even though there is no infection present. Blood vessels dilate; fluid seeps into the surrounding tissue; white blood cells are recruited to the area and inflammatory molecules are released. These factors work together to activate the pain sensing neurons, that then transmit the signal to the brainstem.Glutamate is released from the central terminals, activating a second set of neurons that transmit the signal to the thalamus, and ultimately to higher brain centers, resulting in the perception of pain.
PAR-2 Technology
Currently, no effective treatment for migraines

Neutrophils release elastase, which cleaves PAR-2 very close to the first transmembrane domain, leading to coupling to G12/13 activation and activation of the GTPase, RhoA. Peptides corresponding to the sequence revealed upon elastase cleavage do not mimic the action of the receptor, and it is thought it is the conformational change that occurs upon removal of the entire N-terminus that leads to its activity.

How is PAR-2 involved?

PAR-2 plays a major role in both the initiation and perpetuation of migraine pain, as it is activated by different proteases over the course of a migraine episode. At PARMedics, we are developing small molecule antagonists of PAR-2, which block the release of the neurotransmitters that trigger the inflammatory response, reduce the vasodilation and prevent sensitization of the peripheral nociceptors. Early preclinical studies suggest our PAR-2 antagonists can block pain induced by multiple proteases associated with migraine and do so without crossing the blood-brain barrier. Current migraine medications target only one aspect of the pain pathway, while PAR-2 antagonists have the potential to act at multiple points during a migraine attack.

Chronic Pain

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Asthma

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Tespiratory Infections

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