AABRE: NETWORKING IN PUERTO RICO

PR-AABRE Researcher: Margarita Ortiz–Marciales, Ph.D., Department of Chemistry, UPR, Humacao Campus

Cluster: Drug Design and Delivery and Neuroscience

Collaborators: José Lasalde, Ph.D. (UPR, Río Piedras Campus) and Carmelo García, Ph.D. (UPR, H)

Mentor: John A. Soderquist, Ph.D. (UPR, RP)

Project Title: New Methodologies for the Synthesis of Amino Derivatives as Nicotinic Receptor Agonists

SCIENTISTS IN PUERTO RICO are developing new synthetic drug methodologies and new drugs that could be suitable for treating neuron-degenerative diseases such as Alzheimer’s and Parkinson’s. They are focusing their efforts on drugs that affect the nicotinic acetylcholine receptors (nAChRs), located in a variety of tissues, including the autonomic nervous system, neuromuscular junctions, and brain of vertebrates. These receptors affect almost every human function, including breathing, movement, cognition, memory, and mood. While all acetylcholine receptors respond to the neurotransmitter acetylcholine (ACh), they respond to other molecules as well. The nAChRs are particularly responsive to nicotine.

“In our laboratory we are developing novel methods for the synthesis of organic amino derivatives that can be used in the synthesis of nicotine analogues,” says synthetic organic chemist Margarita Ortiz–Marciales. Nicotine analogues mimic the effects of ACh at the nicotinic receptors.

“The nicotinic acetylcholine receptors are ion channels or gates that are activated by ACh. They were so named because nicotine is an agonist [a substance that binds to a receptor and triggers a response in the cell] for ACh. These receptors are found in a variety of tissues.

“Neuron transmission is caused by ACh’s effects. ACh is formed in the nerve cells, transported in a vesicle to the presynaptic membrane of the nerve endings, and passed to the synaptic cleft, where it is received by the postsynaptic receptors of the next neuron cell. It interacts with the nicotinic receptor to open the sodium channel. This causes a change in the electrical potential for the nerve impulse (depolarization), which is how the information signals are transmitted,” explains Ortiz–Marciales. Nicotinic acetylcholine receptors produce pharmacologically and physiologically distinct responses from other receptors. They are fast in onset, short in duration, and excitatory in nature.

About 20 years ago, scientists developed the cholinergic hypothesis, which posits that Alzheimer’s disease begins as a deficiency in the production of acetylcholine. In fact, four out of the five FDA approved drugs for Alzheimer’s disease on the market today are inhibitors of the enzyme cholinesterase (which breaks down ACh). Although none of these medications stops the disease itself, they may help delay or prevent symptoms from becoming worse for a limited time and may help control some behavioral symptoms. But they have high toxicity and side effects, and scientists are now looking for alternatives. Instead of creating drugs that inhibit the breakdown of ACh, scientists are developing drugs that activate the nAChRs.

“Recently, more selective nicotinic agonists, which like nicotine or ACh activate the receptors, are under development and/or in clinical trial. We plan to develop new and facile synthetic methods to obtain compounds that can be tested for biological activity.”

 

 

mr_ortiz@webmail.uprh.edu