Pirmenol hydrochloride

Pirmenol hydrochloride inhibits IK.ACh by blocking muscarinic receptors. The IC50 of Pirmenol for inhibition of Carbachol-induced IK.ACh is 0.1 μM.

Signaling Pathways >> GPCR/G Protein >> mAChR

Signaling Pathways >> Neuronal Signaling >> mAChR

Signaling Pathways >> Membrane Transporter/Ion Channel >> Potassium Channel

Natural Products >> Alkaloid

Research Areas >> Cardiovascular Disease

IC50: 0.1 μM (IK.ACh)[1]

Pirmenol inhibits the carbachol-induced IK.ACh in a concentration-dependent manner. Pirmenol also inhibits the GTPγS-induced current although the concentrations of Pirmenol needed to inhibit the GTPγS-induced current are much higher than those to inhibit the carbachol-induced IK.ACh. The IC50 of Pirmenol for inhibition of the GTPγS-induced currents is 30 μM. The inhibitory effect of Pirmenol on these IK.ACh is almost completely reversible and the outward current reappeared upon washout of Pirmenol. Pirmenol on the muscarinic acetylcholine receptor-operated K+ current (IK.ACh) in atrial cells and on experimental atrial fibrillation in isolated guinea-pig hearts. In isolated atrial myocytes, Pirmenol concentration dependently inhibits the IK.ACh induced by carbachol or intracellular loading of GTPγS. In Langendorff-perfused hearts Pirmenol reverses the carbachol-induced decreases in effective refractory periods and atrial fibrillation threshold[1].

The pyridine-methanol derivative Pirmenol hydrochloride is a new antiarrhythmic agent. Single-dose studies in rodents demonstrate a 10- to 15-fold difference between the po and iv LD50 values. In rats, the po LD50 is 359.9 mg/kg and the iv LD50 is 23.6 mg/kg. Mice LD50 values are 215.5 and 20.8 mg/kg for po and iv routes, respectively. Short-term subacute iv toxicity studies in rats (2.5, 5.0, and 7.5 mg/kg) and dogs (2.5, 5, and 10 mg/kg) for 4 weeks elicite minimal reactions. Cardiac effects in dogs include drug related increases in heart rate, increases QRS duration, shortening of ST interval without evidence of cardiac tissue damage and mild local reaction at the injection site. Orally, Pirmenol is well tolerated for 13 weeks in rats receiving 25, 50, and 100 mg/kg/day while dogs given 5, 10, and 15 mg/kg/day shows anticholinergic effects at high levels (dryness of mucosae, body tremors). Heart rates are significantly accelerated only at the beginning of the study and QRS changes are seen with wide individual variations. No drug-related tissue changes are elicited in these species. Teratology studies in rats (50, 100, and 150 mg/kg) and in rabbits (10, 25, and 50 mg/kg) show no overt effect on organogenesis but embryotoxicity is seen at 150 mg/kg in rats[2].

Mice and Rats[2] The species and strains used in these studies are: male mice, 21-29 g; rats, 116-261 g; purebred beagle dogs,6.8-12.4 kg;and rabbits, 2.9 kg average. For acute oral and intravenous studies and subacute oral studies, Pirmenol hydrochloride, hereafter referred to as Pirmenol, is supplied as bulk white crystalline compound of approximately 89% purity. Doses are calculated on the basis of base content. In acute studies, Pirmenol is given by gavage as 2 (mice) or 2.5% (rats) in aqueous solution; for iv administration, as 0.5 (mice) or 1% (rats) aqueous solution. In oral subacute studies in dogs, it is given in gelatin capsules, and in rats, it is mixed with the diet to yield the intended dose concentrations. Rabbits received the drug in a 5% aqueous solution by intragastric intubation. For subacute iv studies, Pirmenol is supplied in sterile vials as a 1% solution. In rats, iv injection approximated 0.6 mL/min, and in dogs, the drug is administered via an infusion pump at the rate of 1 mg/kg/min.

[1]. Watanabe Y, et al. Pirmenol inhibits muscarinic acetylcholine receptor-operated K+ current in the guinea pig heart. Eur J Pharmacol. 1997 Oct 29;338(1):71-4.

[2]. Schardein JL, et al. Preclinical toxicology studies with a new antiarrhythmic agent: Pirmenol hydrochloride (CI-845). Toxicol Appl Pharmacol. 1980 Nov;56(2):294-301.

Nigericin sodium salt | Senicapoc | E-4031 | 4-AMINOPYRIDINE | Carbachol | Ginsenoside Rg3 | TRAM-34 | Dofetilide | PAP-1 | Minoxidil | Darifenacin HBr | Flufenamic Acid | Arecoline hydrobromide | Flupirtine maleate | NS-1619

MOLECULAR FORMULA :

C22-H30-N2-O.Cl-H

MOLECULAR WEIGHT :

375.00

WISWESSER LINE NOTATION :

T6NTJ B1 F1 A3XQR&- BT6NJ &GH

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

251 mg/kg

TOXIC EFFECTS :

Behavioral - convulsions or effect on seizure threshold Behavioral - changes in motor activity (specific assay) Lungs, Thorax, or Respiration - dyspnea

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

7900 ug/kg

TOXIC EFFECTS :

Behavioral - changes in motor activity (specific assay) Lungs, Thorax, or Respiration - dyspnea Lungs, Thorax, or Respiration - cyanosis

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

159 mg/kg

TOXIC EFFECTS :

Behavioral - convulsions or effect on seizure threshold Behavioral - changes in motor activity (specific assay) Lungs, Thorax, or Respiration - dyspnea

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

16 mg/kg

TOXIC EFFECTS :

Behavioral - changes in motor activity (specific assay) Lungs, Thorax, or Respiration - dyspnea Lungs, Thorax, or Respiration - cyanosis

TYPE OF TEST :

LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

120 mg/kg

TOXIC EFFECTS :

Behavioral - altered sleep time (including change in righting reflex) Behavioral - ataxia Gastrointestinal - nausea or vomiting

TYPE OF TEST :

LD - Lethal dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

>20 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

18200 mg/kg/1Y-C

TOXIC EFFECTS :

Behavioral - food intake (animal) Blood - changes in serum composition (e.g. TP, bilirubin, cholesterol) Nutritional and Gross Metabolic - weight loss or decreased weight gain

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

5800 mg/kg

SEX/DURATION :

female 15 day(s) pre-mating - 21 day(s) post-birth

TOXIC EFFECTS :

Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

13 gm/kg

SEX/DURATION :

male 9 week(s) pre-mating female 2 week(s) pre-mating - 3 week(s) post-birth

TOXIC EFFECTS :

Reproductive - Maternal Effects - parturition Reproductive - Fertility - pre-implantation mortality (e.g. reduction in number of implants per female; total number of implants per corpora lutea) Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

2800 mg/kg

SEX/DURATION :

female 15-21 day(s) after conception lactating female 21 day(s) post-birth

TOXIC EFFECTS :

Reproductive - Maternal Effects - other effects Reproductive - Effects on Newborn - weaning or lactation index (e.g., # alive at weaning per # alive at day 4) Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

650 mg/kg

SEX/DURATION :

female 6-18 day(s) after conception

TOXIC EFFECTS :

Reproductive - Maternal Effects - other effects

MUTATION DATA

TYPE OF TEST :

Cytogenetic analysis

TEST SYSTEM :

Rodent - hamster Lung

DOSE/DURATION :

1500 mg/L

REFERENCE :

MUREAV Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- Volume(issue)/page/year: 280,205,1992