Receptor-channel research at the interface between academia and pharma

Published on April 2, 2014   33 min
0:00
Hello, my name is Mihaly Hajos. I am from Yale School of Medicine. In my talk, I would like to give you an insight to drug discovery for neurological and psychiatric disorders. I will also focus on some challenges in neuropharmacology and how these obstacles could be addressed by collaborative efforts between academic and pharmaceutical research.
0:26
Use of mind-altering or psychoactive drugs, mostly plants or plant products, dates to prehistoric times. Archaeological findings demonstrated their use dating back at least 10,000 years. Some of these plants, for their active ingredients, are still used or abused today. And some even have found their way to clinical practice.
0:53
However, until very recently, mode of actions of these the mind-altering plants or substances have been totally unknown since it was only in the 20th century that we gained some insight to basic mechanisms of brain function. Nevertheless, artificial modification of mood or sensation by these plants clearly indicated that even the highest level of brain function can be altered, also providing hope for potential treatment of mental disorders. Eventually, a new scientific discipline was born, neuropharmacology, studying drug effects or neural function from molecular to behavioral responses.
1:42
In my talk I will discuss some very pragmatic aspects of neuropharmacology, and drug discovery, and the drug discovery process which is long, tedious, and expensive. I will give real-life examples in drug discovery from our work on alpha-7 nicotinic receptors. I will discuss interactions between academic and pharmaceutical research and some novel trends in this collaboration. However, first I will discuss drug target selection and summarize some fundamentals about drug receptor/ion channel interactions.
2:24
The history of drug discovery for mental or neurological disorders would be best described as serendipity. It started with the discovery more than 50 years ago the sedating effects of the antihistamine agent, chlorpromazine, were also present in agitated psychiatric patients, which opened a new era in psychiatry and anti-psychotic drug research. Soon after the initial findings, it has been recognized that chloropromazine and other related compounds not only induce sensation but also diminish positive symptoms of schizophrenia like hallucination and delusion. Based on these observations, it was revealed that blocking of dopamine-2 receptors underlies the reduction of positive symptoms. And even today almost all our antipsychotic drugs in clinical practice work this way. Today, ideally target selection should be based on genetics or at least understanding the pathophysiology of the disease. However, even until recently it has not been the case due to the polygenic nature of CNS disorders and our limited understanding of brain physiology as well as the pathophysiology of brain illnesses. Therefore, still, target selection is mostly based on understanding the mode of action of currently used medicines, which then frequently lead me to drug discoveries. Clinical, off-target observations are also very useful in the recognition of potential therapeutic application of our currently used drugs.
4:14
So what are the easy ways to interact with brain function or improve this function in the disease? Synapses are attractive sites to interact with neural function such as receptors which are located either pre- or post-synaptically as well as to interact with mechanisms which regulate neurotransmitter release or neurotransmitter elimination such as uptake or the reuptake by neurons and glial cells or interact with enzymes metabolizing neurotransmitters.
4:50
Receptors have been considered as a relatively easy target for drug development. Basically, they can be divided into two categories such as ionotropic receptors and metabotropic receptors. Ionotropic receptors form or are directly linked to ion channels while metabotropic receptors link to secondary messenger systems such as various G-proteins, and in turn, indirectly regulate ion channels. Obviously, opening or closing ion channels will lead to activation or inhibition of the neuron depending on the channel selectivity for cations or anions.
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Receptor-channel research at the interface between academia and pharma

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