Результаты исследований: Научные публикации в периодических изданиях › статья › Рецензирование
Behavioral effects of a potential novel TAAR1 antagonist. / Lam, Vincent M.; Mielnik, Catharine A.; Baimel, Corey; Beerepoot, Pieter; Espinoza, Stefano; Sukhanov, Ilya; Horsfall, Wendy; Gainetdinov, Raul R.; Borgland, Stephanie L.; Ramsey, Amy J.; Salahpour, Ali.
в: Frontiers in Pharmacology, Том 9, № SEP, 953, 04.09.2018.Результаты исследований: Научные публикации в периодических изданиях › статья › Рецензирование
}
TY - JOUR
T1 - Behavioral effects of a potential novel TAAR1 antagonist
AU - Lam, Vincent M.
AU - Mielnik, Catharine A.
AU - Baimel, Corey
AU - Beerepoot, Pieter
AU - Espinoza, Stefano
AU - Sukhanov, Ilya
AU - Horsfall, Wendy
AU - Gainetdinov, Raul R.
AU - Borgland, Stephanie L.
AU - Ramsey, Amy J.
AU - Salahpour, Ali
PY - 2018/9/4
Y1 - 2018/9/4
N2 - The trace amine associated receptor 1 (TAAR1) is a G-protein coupled receptor expressed in the monoaminergic regions of the brain, and represents a potential novel therapeutic target for the treatment of neurological disorders. While selective agonists for TAAR1 have been successfully identified, only one high affinity TAAR1 antagonist has been described thus far. We previously identified four potential low potency TAAR1 antagonists through an in silico screen on a TAAR1 homology model. One of the identified antagonists (compound 22) was predicted to have favorable physicochemical properties, which would allow the drug to cross the blood brain barrier. In vivo studies were therefore carried out and showed that compound 22 potentiates amphetamine- and cocaine-mediated locomotor activity. Furthermore, electrophysiology experiments demonstrated that compound 22 increased firing of dopamine neurons similar to EPPTB, the only known TAAR1 antagonist. In order to assess whether the effects of compound 22 were mediated through TAAR1, experiments were carried out on TAAR1-KO mice. The results showed that compound 22 is able to enhance amphetamine- and cocaine-mediated locomotor activity, even in TAAR1-KO mice, suggesting that the in vivo effects of this compound are not mediated by TAAR1. In collaboration with Psychoactive Drug Screening Program, we attempted to determine the targets for compound 22. Psychoactive Drug Screening Program (PDSP) results suggested several potential targets for compound 22 including, the dopamine, norepinephrine and serotonin transporters; as well as sigma 1 and 2 receptors. Our follow-up studies using heterologous cell systems showed that the dopamine transporter is not a target of compound 22. Therefore, the biological target of compound 22 mediating its psychoactive effects still remains unknown.
AB - The trace amine associated receptor 1 (TAAR1) is a G-protein coupled receptor expressed in the monoaminergic regions of the brain, and represents a potential novel therapeutic target for the treatment of neurological disorders. While selective agonists for TAAR1 have been successfully identified, only one high affinity TAAR1 antagonist has been described thus far. We previously identified four potential low potency TAAR1 antagonists through an in silico screen on a TAAR1 homology model. One of the identified antagonists (compound 22) was predicted to have favorable physicochemical properties, which would allow the drug to cross the blood brain barrier. In vivo studies were therefore carried out and showed that compound 22 potentiates amphetamine- and cocaine-mediated locomotor activity. Furthermore, electrophysiology experiments demonstrated that compound 22 increased firing of dopamine neurons similar to EPPTB, the only known TAAR1 antagonist. In order to assess whether the effects of compound 22 were mediated through TAAR1, experiments were carried out on TAAR1-KO mice. The results showed that compound 22 is able to enhance amphetamine- and cocaine-mediated locomotor activity, even in TAAR1-KO mice, suggesting that the in vivo effects of this compound are not mediated by TAAR1. In collaboration with Psychoactive Drug Screening Program, we attempted to determine the targets for compound 22. Psychoactive Drug Screening Program (PDSP) results suggested several potential targets for compound 22 including, the dopamine, norepinephrine and serotonin transporters; as well as sigma 1 and 2 receptors. Our follow-up studies using heterologous cell systems showed that the dopamine transporter is not a target of compound 22. Therefore, the biological target of compound 22 mediating its psychoactive effects still remains unknown.
KW - Amphetamine
KW - Cocaine
KW - Dopamine transporter (DAT)
KW - Electrophysiology
KW - Locomotor activity
KW - TAAR1
KW - MESOLIMBIC SYSTEM
KW - cocaine
KW - dopamine transporter (DAT)
KW - BASAL GANGLIA
KW - amphetamine
KW - AMINE-ASSOCIATED RECEPTOR
KW - COCAINE
KW - DOPAMINE TRANSPORTER
KW - AGONISTS
KW - electrophysiology
KW - ADENOSINE A(2A) RECEPTORS
KW - IN-VIVO
KW - ANIMAL-MODELS
KW - locomotor activity
KW - SIGMA-1 RECEPTOR
UR - http://www.scopus.com/inward/record.url?scp=85053169049&partnerID=8YFLogxK
U2 - 10.3389/fphar.2018.00953
DO - 10.3389/fphar.2018.00953
M3 - Article
AN - SCOPUS:85053169049
VL - 9
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
SN - 1663-9812
IS - SEP
M1 - 953
ER -
ID: 36295102