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Volume 08
Clinical Pharmacology & Biopharmaceutics
ISSN: 2167-065X
Page 48
August 19-20, 2019 Vienna, Austria
&
7
th
World Heart Congress
24
th
World Congress on
Pharmacology
Pharmacology 2019
World Heart Congress 2019
August 19-20, 2019
JOINT EVENT
conference
series
.com
Jahanshah Amin, Clin Pharmacol Biopharm, Volume 08
A ketoxime analogue of ketamine with distinct molecular actions on GABAA and NMDA
receptors demonstrates superior antidepressant activity
D
issociative anesthetic ketamine can rapidly alleviate symptoms of psychiatric depression with prolonged duration
of action. Despite the promise, untoward psycho-mimetic manifestations of ketamine have curbed its clinical
application. In a search for a ketamine substitute with higher antidepressant activity and lower side effects, we synthesized
several novel ketamine analogs and tested them
in vitro
and
in vivo
. A ketoxime analog, termed oximeamine, shows
the following pharmacological properties compared to ketamine: First, oximeamine potentiates the activity of GABA
A
receptors, specifically that of cerebellar
α
6
β
2
δ
subtype, with higher potency. Second, oximeamine blocks NMDA receptors
with similar potency and efficacy yet associates with (on-rate) and dissociates from (off-rate) the NMDA receptors at
a significantly faster rate. The relatively faster on- and off-rate of oximeamine appears most prominent at the NMDA
NR1/NR2B receptor subtype. Third, neither oximeamine nor ketamine display any significant action on AMPA receptor
subtypes. Finally, in forced swim test, oximeamine demonstrates a significantly greater antidepressant activity than
ketamine. In conclusion, the differential yet lower intensity block of the NMDA receptor subtypes and the higher activity
on the GABAA receptors, together with the more robust antidepressant activity herald the superiority of oximeamine
over ketamine with higher antidepressant efficacy and lower side effects.
Recent Publications
1.
Walters RJ, Hadley SH, Morris KDW, and Amin J: Benzodiazepines act upon GABA
A
receptors via two distinct and
separable mechanisms. (2000) Nature Neuroscience; 3(12): 1274-1281.
2.
Hevers W, Hadley SH, Lüddens H, Amin J: Ketamine, But Not Phencyclidine, Selectively Modulates Cerebellar GABA
A
Receptors Containing
α
6
and
δ
Subunits. (2008) Journal of Neuroscience 28(20): 5383-5393.
3.
Morris KW and Amin J: Insight into the mechanism of action of neuroactive steroids. (2004) Mol Pharmacol; 66:56-69.
4.
Hadley SH & Amin J: Rat
α
6
β
2
δ
GABA
A
receptors exhibit two distinct and separable agonist affinities. (2007) Journal
of Physiology 581.3:1001-1018.
5.
Amin J, Subbarayan MS. Orthosteric-versus allosteric-dependent activation of the GABAA receptor requires
Jahanshah Amin
University of South Florida, USA