Platform Programs
Adenosine Receptor Programs
Adenosine is a multi-purpose signal molecule that regulates a variety of cellular functions and is released under conditions of physiological stress. The actions of adenosine are mediated through four receptors subtypes (A1, A2A, A2B and A3).
Adenosine acts at the A1 receptor subtype to cause decreases in heart rate, force of contraction, and responsiveness to adrenaline, and at the A2A receptor subtype to cause dilation of coronary arteries to enhance blood flow to the heart. In the central nervous system (CNS), adenosine, released during episodes of epilepsy or as a consequence of hypoxia or stroke, acts at the A1 receptor subtype to exert a neuroprotective action by decreasing electrical excitability, inhibiting the release of excitatory amino acids (EAA) and acts at the A2A receptor subtype to increase cerebral blood flow.
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Effect of Receptor Activation |
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| A1 |
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Heart Rhythm- decrease in heart rate, force of atrial contraction, and responsiveness to adrenaline |
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Wakefulness- decrease in electrical excitability and inhibition of excitatory amino acid (EAA) release |
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Anti-diuresis |
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Anti-lipolytic
Insulin enhancer
Antihypertensive
Wound healing
Hair growth |
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| A2A |
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Regulates blood vessel tone - dilation of the coronary arteries supplying blood to the heart muscle |
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Anti-inflammatory -cerebral blood flow increase |
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Wound healing |
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| A2B |
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Allergic Responses
GI Tract Relaxation
Anti-inflammatory |
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| A3 |
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Cardioprotective |
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Allergic Responses |
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Mechanism of Coupling
Adenosine binds to the receptor subtypes and activates the receptors to produce G proteins. As shown in the following schematic, G proteins themselves can either stimulate (Gs) or inhibit (Gi) the enzyme adenylate cyclase so as to generate or prevent the manufacture of cyclic AMP. In addition, G coupled proteins can open potassium channels in cardiac tissue, resulting in depression of cardiac electrical activity.
Selective vs Non-Selective Drugs
The use of adenosine itself or non-selective agonist drugs stimulates all receptor subtypes. This brings on a desired effect but may also cause unwanted side effects. Development of adenosine analogs, however, creates a new class of medicines that are subtype-selective and avoid potentially harmful side effects.
Aderis has a broad intellectual property estate that encompasses selective adenosine agonists that mimic the action of adenosine, and selective adenosine antagonists that oppose the actions of adenosine at receptor subtypes. We have several products in our development pipeline in various stages of clinical development.
References:
Dopamine Receptor Platform
The human nervous system is composed of billions of specialized cells called neurons. Efficient communication between these cells is crucial to the normal functioning of the central and peripheral nervous systems. In some ways, neurons act like computers. They receive messages, process those messages and send out the results as new messages to other cells. In the case of neurons, the message consists of chemicals called neurotransmitters which interact with receptors on the outer surface of the cell membrane.
Dopamine is a small-molecule neurotransmitter involved in the control of both motor and emotional behavior. Despite the large number of crucial functions it performs, this chemical messenger is found in a relatively small number of brain cells. Abnormalities in dopamine regulation are implicated in a number of neurological and psychiatric disorders.
There are five subtypes of dopamine receptors (D1, D2, D3, D4, and D5) which are all G protein-coupled receptors. These receptors can be differentiated pharmacologically, biologically, physiologically and by their anatomical distribution. They exert their biological activity by coupling to and activating different G protein complexes. Activation of D1 and D5 receptors results in stimulation of adenylate cyclase via Gs proteins, whereas D2, D3, and D4 receptor activation lead to inhibition of adenylate cyclase via Gi proteins to inhibit cyclic AMP production.
Parkinson's disease is a result of a lack of dopamine due to progressive destruction of nerves supplying dopamine. Consequently there is a lack of dopamine receptor stimulation in the central nervous system. Our dopamine agonist drugs replace the missing dopamine and moreover selectively activate the D2 receptor subtype to avoid side effects associated with the activation of the other subtypes. Our product candidate, Rotigotine CDS, is a D2 agonist administered using a transdermal patch and currently in Phase III clinical trials for the treatment of Parkinson's disease.
Alternatively, dopamine antagonists are drugs that bind but don't stimulate dopamine receptors. Antagonists can prevent or reverse the actions of dopamine by keeping dopamine from attaching to receptors. Antagonists are traditionally used to treat schizophrenia and related mental disorders.
Aderis has a broad intellectual property estate that encompasses selective dopamine agonists, transdermal formulations and bulk manufacturing processes for these compounds.
References:
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