Pharmacological and Neurotoxicological Actions Mediated By Bupropion and Diethylpropion

Hugo R. Arias, Abel Santamaría, Syed F. Ali

Research output: Contribution to journalReview article

23 Citations (Scopus)

Abstract

The antiappetite agent diethylpropion (DEP), and the antidepressant and antismoking aid compound bupropion (BP), not only share the same structural motif but also present similar mechanisms of action in the CNS. For example, both drugs induce the release as well as inhibit the reuptake of neurotransmitters such as a dopamine (DA) and norepinephrine (NE). In general, they produce mild side effects, including reversible psychomotor alterations mostly in geriatric patients (by BP), or moderate changes in neurotransmitter contents linked to oxidative damage (by DEP). Therefore, attention must be paid during any therapeutic use of these agents. Regarding the interaction of BP with the DA transporter, residues S359, located in the middle of TM7, and A279, located close to the extracellular end of TM5, contribute to the binding and blockade of translocation mediated by BP, respectively. Additional mechanisms of action have also been determined for each compound. For example, BP is a noncompetitive antagonist (NCA) of several nicotinic acetylcholine receptors (AChRs). Based on this evidence, the dual antidepressant and antinicotinic activity of BP is currently considered to be mediated by its stimulatory action on DA and NE systems as well as its inhibitory action on AChRs. Considering the results obtained in the archetypical mouse muscle AChR, a sequential mechanism can be hypothesized to explain the inhibitory action of BP on neuronal AChRs: (1) BP first binds to AChRs in the resting state, decreasing the probability of ion channel opening, (2) the remnant fraction of open ion channels is subsequently decreased by accelerating the desensitization process, and finally (3) BP interacts with a binding domain located between the serine (position 9′) and valine (position 13′) rings that is shared with the NCA phencyclidine and other tricyclic antidepressants. The homologous location in the α3β4 AChR is between the serine and valine/phenylalanine rings. This new evidence opens a window for further investigation using AChRs as targets for the action of safer antidepressants and novel antiaddictive compounds.

Original languageEnglish
Pages (from-to)223-255
Number of pages33
JournalInternational Review of Neurobiology
Volume88
Issue numberC
DOIs
StatePublished - 16 Dec 2009
Externally publishedYes

Fingerprint

Diethylpropion
Bupropion
Cholinergic Receptors
Pharmacology
Antidepressive Agents
Valine
Ion Channels
Serine
Neurotransmitter Agents
Dopamine
Norepinephrine
Phencyclidine
Dopamine Plasma Membrane Transport Proteins
Tricyclic Antidepressive Agents
Nicotinic Receptors
Therapeutic Uses
Phenylalanine
Geriatrics

Cite this

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title = "Pharmacological and Neurotoxicological Actions Mediated By Bupropion and Diethylpropion",
abstract = "The antiappetite agent diethylpropion (DEP), and the antidepressant and antismoking aid compound bupropion (BP), not only share the same structural motif but also present similar mechanisms of action in the CNS. For example, both drugs induce the release as well as inhibit the reuptake of neurotransmitters such as a dopamine (DA) and norepinephrine (NE). In general, they produce mild side effects, including reversible psychomotor alterations mostly in geriatric patients (by BP), or moderate changes in neurotransmitter contents linked to oxidative damage (by DEP). Therefore, attention must be paid during any therapeutic use of these agents. Regarding the interaction of BP with the DA transporter, residues S359, located in the middle of TM7, and A279, located close to the extracellular end of TM5, contribute to the binding and blockade of translocation mediated by BP, respectively. Additional mechanisms of action have also been determined for each compound. For example, BP is a noncompetitive antagonist (NCA) of several nicotinic acetylcholine receptors (AChRs). Based on this evidence, the dual antidepressant and antinicotinic activity of BP is currently considered to be mediated by its stimulatory action on DA and NE systems as well as its inhibitory action on AChRs. Considering the results obtained in the archetypical mouse muscle AChR, a sequential mechanism can be hypothesized to explain the inhibitory action of BP on neuronal AChRs: (1) BP first binds to AChRs in the resting state, decreasing the probability of ion channel opening, (2) the remnant fraction of open ion channels is subsequently decreased by accelerating the desensitization process, and finally (3) BP interacts with a binding domain located between the serine (position 9′) and valine (position 13′) rings that is shared with the NCA phencyclidine and other tricyclic antidepressants. The homologous location in the α3β4 AChR is between the serine and valine/phenylalanine rings. This new evidence opens a window for further investigation using AChRs as targets for the action of safer antidepressants and novel antiaddictive compounds.",
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Pharmacological and Neurotoxicological Actions Mediated By Bupropion and Diethylpropion. / Arias, Hugo R.; Santamaría, Abel; Ali, Syed F.

In: International Review of Neurobiology, Vol. 88, No. C, 16.12.2009, p. 223-255.

Research output: Contribution to journalReview article

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