Understanding Neurotransmitters Is Key to New Drug R&D

Today it is common knowledge that nerves communicate by chemical release using neurotransmitters. In the past, however, some scientists held a different opinion. Pharmacologists and neurophysiologists waged an ongoing battle. Neurophysiologists did not accept the fact that chemical release would be quick enough to activate skeletal muscles. They believed that electrical transmission was the only explanation, and they refuted the theory that nerve impulses at brain synapses were innervated by any form of chemical secretion. Two fascinating recent books cover all the details of this controversy.1,2The Autonomic System

To understand the mechanism of communication between nerve cells, pharmacologists studied the structure of nerves themselves, including the gap between neurons and between neurons and the muscles they innervate. Much of this research was described in Sir Charles Sherrington's book, The Integrative Action of the Nervous System.3 Sherrington also was the first person to use the term synapse.4The autonomic system consists of nerve cells and fibers of 2 differently functioning types, comprising the sympathetic and parasympathetic systems. Nerve cells or neurons contain a cell body, a number of branched dendrites, and an axon, which carries impulses toward other neurons and their dendrites.^{5 Nerve impulses are tiny charges of electricity that are created when certain chemical or physical changes take place in a nerve cell or fiber in response to stimulation. When the signal reaches a synapse, it causes the molecules of a neurotransmitter to be released from the axon into the junction. There they bind to the receptor molecules on the branches of a dendrite or cell membrane of the target cell, opening or closing channels on that membrane and thereby initiating a current flow. The action potential exerts either an excitatory effect or an inhibitory effect on the target neuron. The action is completed in milliseconds.}1

Chemical Messengers

The various components of the autonomic nervous system use different chemical messengers. Parasympathetic nerves release acetylcholine as the neurotransmitter. Cells of the sympathetic cholinergic system also release acetylcholine. Norepinephrine is the main neurotransmitter used by the sympathetic nervous system for regulating circulation.

Pharmacologists have discovered much more about different chemicals that act as stimulators or inhibitors. In addition to acetylcholine and the biogenic amines (norepinephrine, epinephrine, dopamine, serotonin, histamine), other neurotransmitters include gamma aminobutyrate, glutamate, aspartate, glycine, adenosine, adenosine triphosphate, and nitric oxide.6 Acetylcholine is the only major neurotransmitter not derived directly from an amino acid. Each neurotransmitter molecule has a unique 3-dimensional structure that differentiates it from all others. The receptor molecule on the target molecule also has a specific structure.7Gamma aminobutyric acid (GABA) was the first amino acid suspected to be an inhibitory neurotransmitter. It acts by binding to specific receptors in the plasma membrane of pre- and postsynaptic neurons. This binding causes the opening of ion channels to allow the flow of negatively charged chloride ions into the cell. Many drugs that act as agonists of GABA receptors (eg, benzodiazepines, valproate) or increase the amount of GABA have relaxing, antianxiety, and anticonvulsive effects.1The first suggestion that glutamate might be a neurotransmitter came from observations by Curtis and Watkins in the late 1950s and early 1960s.8 Glutamate is the major excitatory neurotransmitter in the brain, and neural damage following vascular stroke is attributable in large part to a massive release of glutamate. Glutamate also plays a major role in drug addiction. Nitric oxide, a gas, activates soluble guanylyl cyclase to form cyclic guanosine monophosphate, which has multiple effects on the body.9By the early 1970s, the molecular effects of neurotransmitters were clarified. Many other neurotransmitters were found to be derived from precursor proteins - the so-called peptide neurotransmitters. Over the past few decades, up to 100 novel neurotransmitter candidates have been identified, and much more has been learned about earlier neurotransmitters. 8 For example, dopamine also can act as a toxic substance exacerbating the pathogenetic process of Parkinson's disease when continually released from vesicles into the cytoplasm. The release is due to newly discovered protein aggregates that impair cell function.10

New Drug Development

Understanding the effects of neurotransmitters is extremely important in therapeutics. All psychiatric drugs act by affecting neurotransmitters. Understanding their mechanism of action and adverse effects is key to developing new drugs.

Moreover, one half of all medicines prescribed today have something in common: at the molecular level, they act on the same type of target. The target is a serpentine protein that weaves through the membrane that envelops the cell. Their external parts serve as an antenna for molecular signals as they approach the cell, and internal parts trigger the cell's responses to cues, such as activating a signal processor called a Gprotein. The serpents themselves are thus known as G-protein coupled receptors, or GPCRs.11 These receptors respond to neurotransmitters that are only a few times as large as a single carbon atom, all the way up to proteins 75 times as large.

Drugs that target these receptors are diverse. The list includes blood pressure reducers (eg, propranolol), stomach acid suppressors (eg, ranitidine), bronchodilators (eg, albuterol), and antidepressants (eg, paroxetine). The GPCR-targeting drugs work in 1 of 2 ways. They either

attach to the "antenna" region of the receptor and mimic the effect of the natural neurotransmitter, hormone, or other molecule that normally sends signals through the GPCR, or they interfere with a natural signaler's ability to act on the antenna.

The neurotransmitter norepinephrine activates 2 types of GPCRs, called alpha and beta adrenoceptors. These various receptors govern life-sustaining processes. In the heart, beta1 adrenoceptors quicken the heart rate and increase the force of each beat. In the lungs, beta2 adrenoceptors widen the air passages.11Final Thoughts

The advent of genomic science, rapid DNA sequencing, combinatorial chemistry, cell-based assays, and automated throughput screening have enhanced the process of drug discovery.12 These techniques, coupled with new molecular revelations about neurotransmitters, will facilitate the development of an array of new drugs.We now know that there are at least 4 different glutamate receptors and 6 dopamine receptors, and serotonin may have as many as 15. According to some estimates, as many as 100 different chemical substances may be secreted by brain neurons.1

An exciting era is dawning for pharmacologists searching for new drugs or for scientists still trying to discover the mechanism of action for older drugs.

References

• Valenstein ES. The War of the Soups and the Sparks. New York, NY: Columbia University Press; 2005.
• Donnerer J, Lembeck F. The Chemical Languages of the Nervous System. Basel, Switzerland: Karger; 2006.
• Sherrington CS. The Integrative Action of the Nervous System. New Haven, Conn: Yale University Press, 1906 [reprinted 1947].
• Bennett M. History of the Synapse. Melbourne, Australia: Harwood Academic Publishers; 2001.
• Nuland SB. The Wisdom of the Body. New York, NY: Knopf; 1997.
• http://web.indstate.edu/theme/mwking/nerves.html. Accessed August 24, 2006.
• Restak RM. Receptors. New York, NY: Bantam Books; 1994.
• Snyder SH/ Forty years of neurotransmitters; a personal account. Arch Gen Psychiatry. 2002;59:983-994.
• Murad F. Nitric oxide and cyclic GMP in cell signaling and drug development. N Engl J Med. 2006;355(19):2003-2011.
• Golbe LI. Neurogeneration in the age of molecular biology. BMJ. 2002;324:1467-1468.
• Kenakin T. New bull?s eyes for drugs. Sci Am. 2005;293:51-57.
• Drews J. Drug discovery: a historical perspective. Science. 2000;287:1960-1964.