TY - JOUR
T1 - Pharmacological and Neurotoxicological Actions Mediated By Bupropion and Diethylpropion
AU - Arias, Hugo R.
AU - Santamaría, Abel
AU - Ali, Syed F.
N1 - Funding Information:
This research was supported by grants from the Science Foundation Arizona and Stardust Foundation and the Office of Research and Sponsored Programs, Midwestern University (to H. R.), and from the Consejo Nacional de Ciencia y Tecnología (CONACYT 48370-Q), Mexico (to A. S.).
PY - 2009/12/16
Y1 - 2009/12/16
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=71749086137&partnerID=8YFLogxK
U2 - 10.1016/S0074-7742(09)88009-4
DO - 10.1016/S0074-7742(09)88009-4
M3 - Review article
C2 - 19897080
AN - SCOPUS:71749086137
SN - 0074-7742
VL - 88
SP - 223
EP - 255
JO - International Review of Neurobiology
JF - International Review of Neurobiology
IS - C
ER -