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Details

Stereochemistry ACHIRAL
Molecular Formula C29H43N2O4
Molecular Weight 483.6627
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 1

SHOW SMILES / InChI
Structure of OTILONIUM

SMILES

CCCCCCCCOC1=CC=CC=C1C(=O)NC2=CC=C(C=C2)C(=O)OCC[N+](C)(CC)CC

InChI

InChIKey=NQHNLNLJPDMBFN-UHFFFAOYSA-O
InChI=1S/C29H42N2O4/c1-5-8-9-10-11-14-22-34-27-16-13-12-15-26(27)28(32)30-25-19-17-24(18-20-25)29(33)35-23-21-31(4,6-2)7-3/h12-13,15-20H,5-11,14,21-23H2,1-4H3/p+1

HIDE SMILES / InChI

Description

Otilonium is a musculotropic spasmolytic agent belonging to the family of quaternary ammonium derivatives and successfully used in the treatment of patients affected by Irritable bowel syndrome (IBS) due to its specific pharmacokinetic and pharmacodynamic properties. The positive polarity of the head of the Otilonium molecule determines the main pharmacokinetic property of this drug: a minimal systemic absorption and the consequently high safety profile. Studies on animal models revealed a specific Otilonium accumulation in colonic circular muscle at therapeutic µm concentrations, while its plasma levels were 1000 times lower, together with a poor penetration of the drug in the central nervous system. Consistently, after oral administration to healthy volunteers, the Otilonium plasmatic concentration was very low, less than 1% of the drug was eliminated by urine, and 97% was eliminated by feces. Recent clinical studies showed comparable safety and tolerability for Otilonium and placebo. Otilonium was shown to inhibit the main patterns of human sigmoid motility in vitro, including: the tone of smooth muscle cells (SMCs); the rhythmic phasic contractions induced by the interstitial cells of Cajal; and the strong contractions induced by stimulation of enteric motor neurons mainly by blocking the calcium influx through L-type calcium channels on SMCs. Recent in vitro studies using cultured human colonic SMCs to further assess the musculotropic spasmolytic properties of Otilonium confirmed that this drug causes smooth muscle relaxation through the inhibition of voltage-gated calcium channels (L-type > T-type) and the inhibition of muscarinic and tachykinergic effects.

CNS Activity

Originator

Approval Year

Targets

Primary TargetPharmacologyConditionPotency
54.7 nM [IC50]
400.0 nM [IC50]
222.0 nM [IC50]
156.0 nM [IC50]
1490.0 nM [IC50]

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Obimal

PubMed

Patents

Sample Use Guides

In Vivo Use Guide
3 tablets (3 × 40 mg) daily before meals (120 mg Otilonium/day)
Route of Administration: Oral
In Vitro Use Guide
Human circular smooth muscle cells were used for activity evaluation. To determine the effect of Otilonium on ionic conductances in human jejunal circular smooth muscle, we patch clamped enzymatically dissociated cells with Cs+ in the pipette to block outward K+ currents and with NaCl or NMDG-Cl Ringer’s extracellular solution. Electrodes were coated with R6101 (Dow Corning, Midland, MI, USA) and fire polished to a final resistance of 3–5 M. Currents were amplified, digitized and processed using an Axopatch 200B amplifier, a Digidata 1200, and pCLAMP 8 software (Axon Instruments, Foster City, CA, USA). In experiments examining Na+ or Ca2+ current, whole cell records were sampled at 10 kHz and filtered at 4 kHz with an eight-pole Bessel filter. For these experiments, cells were held at -100 mV and pulsed from -80 to +35 mV in 5 mV intervals for 50 ms. Otilonium (0.09–9 mkM) was used as this reproduced clinical intracellular concentrations. In human circular smooth muscle cells, Otilonium inhibited L-type Ca2+ current by 25% at 0.9 mkM and 90% at 9 mkM.