Dopamine beta-hydroxylase is an enzyme that catalyzes the conversion of dopamine to norepinephrine. Nepicastat hydrochloride is a dopamine β-hydroxylase inhibitor with IC50 of 8.5 ± 0.8 and 9.0 ± 0.8 nM for bovine and human, respectively[3]. In vitro, Nepicastat hydrochloride exhibited selective and concentration-dependent inhibition to dopamine-β-hydroxylase in cattle and humans, with IC50 value of 8.5 nM and 9.0 nM, respectively. Nepicastat hydrochloride has quite low affinity for 12 other enzymes and 13 neurotransmitter receptors. In vivo, in the arteries, the left ventricle, and the cerebral cortex of rats with spontaneous hypertension (SHRs), Nepicastat dosage dependently decreased the level of norepinephrine, and increased the dopamine content and dopamine/norepinephrine ratio[3]. In rat brains, 50 mg/kg (i.p.) dose of Nepicastat hydrochloride led to reduction in the noradrenalin (NE), and block of the recovery of cocaine induced drug addiction [4]. In dogs with chronic heart failure, low doses of nepicastat (0.5 mg/kg) are quite suitable to prevent dysfunction and remodeling of the left ventricle (LV), and the combination of nepicastat hydrochloride and enalapril is quite suitable to use in addition to all morphological characteristics[5]. Nepicastat hydrochloride (3 mg/kg, i.v.), to be quite suitable for the use in SHRs anesthesia, plays the role of antihypertensive; it significantly reduces renal vascular resistance (38%) and increases renal blood flow (22%)[6].
Nepicastat HCl/盐酸内匹司他 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Human neuroblastoma cell line SK-N-SH
9.0±0.8 nM (IC50)
30–40 minutes
To evaluate the inhibitory effect of Nepicastat on dopamine-β-hydroxylase in human neuroblastoma cell line SK-N-SH, results showed that Nepicastat effectively inhibited enzyme activity
Br J Pharmacol. 1997 Aug;121(8):1803-9
Bovine adrenal dopamine-β-hydroxylase
8.5±0.8 nM (IC50)
30–40 minutes
To evaluate the inhibitory effect of Nepicastat on bovine adrenal dopamine-β-hydroxylase, results showed that Nepicastat effectively inhibited enzyme activity
Br J Pharmacol. 1997 Aug;121(8):1803-9
Nepicastat HCl/盐酸内匹司他 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Rats
Cocaine discrimination training model
Intraperitoneal injection
0–56.0 mg/kg
Single administration, 2 hours before testing
To evaluate the effect of Nepicastat on the discriminative stimulus effects of cocaine. Results showed that Nepicastat alone did not produce cocaine-like stimulus effects but enhanced the discriminative stimulus effects of cocaine when combined.
J Pharmacol Exp Ther. 2013 Dec;347(3):564-73
Squirrel monkeys
Cocaine self-administration and reinstatement model
Intramuscular injection
10 and 30 mg/kg
Acute administration 30 minutes to 24 hours prior or subchronic administration for 5 consecutive days
To evaluate the effects of DBH inhibition on cocaine-induced reinstatement behavior. Results showed that nepicastat did not significantly alter cocaine-induced reinstatement but induced a modest reinstatement effect when administered alone under 30-minute pretreatment conditions.
J Pharmacol Exp Ther. 2014 Jul;350(1):144-52
C57BL/6N mice
Chronic intermittent hypoxia (CIH)-induced lung cancer model
Oral gavage
10 mg/kg
Once daily for four weeks
Nepicastat significantly inhibited CIH-induced murine lung tumor growth, reduced the expression of Ki-67, cyclin D1, CD31, VEGFR2, PD-1, and PD-L1 in tumor tissues, and decreased inflammatory cytokine levels in peripheral blood.
Respir Res. 2024 Sep 28;25(1):347
Spontaneously hypertensive rats (SHRs)
Spontaneously hypertensive rat model
Oral
3, 10, 30 or 100 mg/kg
Three consecutive doses, 12 hours apart
To evaluate the effect of Nepicastat on tissue catecholamine levels in spontaneously hypertensive rats, results showed that Nepicastat dose-dependently reduced noradrenaline content and increased dopamine content
Br J Pharmacol. 1997 Aug;121(8):1803-9
Female mice (129x1/SvJ)
Post-traumatic stress disorder (PTSD) animal model
Oral
30 mg/kg
Once daily from day 0 to day 7 or 12
To evaluate if nepicastat treatment decreases PTSD signs. Results showed that nepicastat treatment decreased freezing behavior, increased time spent and entries in open arms in the elevated plus maze test, decreased adrenal DBH activity and catecholamines in plasma and tissues, and increased hippocampal Npas4 and Bdnf mRNA expression.
Front Mol Neurosci. 2021 Sep 24;14:745219
Mice
Dopamine transporter knockout mice
Intraperitoneal injection
40 mg/kg
Single administration
Inhibited hyperactivity in DAT-KO mice, reduced NE levels and elevated DA levels in PFC tissue without altering 5-HT levels
Sci Rep. 2022 Feb 24;12(1):3129
Rats
Cocaine-seeking behavior model
Intraperitoneal injection
5, 50, or 100 mg/kg
Single dose
Evaluate the effect of Nepicastat on cocaine-seeking behavior. It was found that Nepicastat significantly lowered the breakpoint for cocaine and attenuated reinstatement induced by drug-associated cues, footshock, and yohimbine.
Neuropsychopharmacology. 2013 May;38(6):1032-8
Rats
Cocaine self-administration and reinstatement model
Intraperitoneal injection
50 mg/kg
Single dose, measured after 2 hours
To evaluate the effects of Nepicastat on cocaine-induced reinstatement behavior. Nepicastat at a dose of 50 mg/kg significantly reduced brain NE levels and completely blocked cocaine-primed reinstatement.
Neuropsychopharmacology. 2010 Nov;35(12):2440-9
Rats
Cocaine self-administration model
Intraperitoneal injection
50 mg/kg
Single dose, 2 hours before testing
To investigate the effect of Nepicastat on cocaine-induced reinstatement behavior, results showed that Nepicastat blocked cocaine-primed reinstatement
Neuropharmacology. 2017 Jun;119:134-140
Rats
Intravenous morphine self-administration model
Intraperitoneal injection
6.25–50 mg/kg
Single or 14-day repeated administration
To evaluate the effects of Nepicastat on morphine self-administration and seeking behavior. Results showed that Nepicastat reduced active lever presses and attenuated reinstatement of seeking behavior.
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