Alpharmagen has a portfolio of exceedingly potent positive allosteric modulators (PAMs) of the α7 nicotinic acetylcholine receptor (nAChR) that penetrate into the brain with high efficiency. We are currently preparing compounds for testing in human clinical trials with the goal to improve cognition in diseases like schizophrenia and Alzheimer’s disease.

The α7 nAChR is an ion channel present in the brain, spleen, and white blood cells. The channel is activated by its natural ligands such as choline, acetylcholine, and others such as nicotine. These activators, or agonists, promote current to flow through the channel. In certain diseases such as in schizophrenia, there is a reduced number of α7 nAChRs in the brain and therefore the overall function of the nAChR system is diminished. While direct activation of the α7 nAChR is an effective method for improving its function, overstimulation of the receptor can cause it to shutdown or desensitize.

PAMs act through a different mechanism than direct agonists. These allosteric modulators bind to a different site on the receptor, called an allosteric site, and do not invoke current on their own. PAMs work together with agonists to produce the necessary current. They act to stabilize the receptor so that binding of agonists, such as acetylcholine or nicotine, produce current more efficiently. In this way, the amount of current invoked through acetylcholine in the presence of a PAM, for example, will be more than in the presence of the same amount of acetylcholine alone. These so called Type 1 PAMs have the additional benefit of getting efficient current conduction without changing the kinetics of the receptor (i.e. they do not invoke a current on their own nor do they lock the receptor in an open, sensitized state).

These PAMs have shown positive cognitive improvement in animal models and have great potential for use in human cognitive diseases like schizophrenia and Alzheimer’s disease. Alpharmagen is excited about the prospects for these drugs and is actively preparing them for testing in human clinical trials.

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