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E u r o p e a n C o n g r e s s o n
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A u g u s t 1 3 - 1 4 , 2 0 1 8
P a r i s , F r a n c e
American Journal of Pharmacology and Pharmacotherapeutics
ISSN: 2393-8862
T
he N-decyltropine chloride synthesized by us (IEM-1556), which was previously shown to be an selective blocker of nicotinic
cholinergic receptors of parasympathetic ganglia, also revealed the properties of a strong analgesic, which cannot be
explained only by its central anticholinergic action in the view of lack of significant analgesic activity in a reference such as
central nicotinic receptor antagonist, mecamylamine. Earlier, we obtained data in favor of the participation of adenosine and
vagal afferents in the development of the analgesic effect of IEM-1556. The essence of the proposed hypothesis is the ability
of IEM-1556 to release endogenous adenosine, stimulating subdiaphragmal vagal afferents as a key link in the mechanism of
analgesic action of the drug. In our recent paper, we presented experimental data in favor of this hypothesis. As the reference
drug, adenosine was used which had the highest analgesic activity in the tail-flick test in rats associated with stimulation of the
vagal afferents of the gastric mucosa. Adenosine in a dose of 22-30 mg/kg and IEM-1556 (N-decyltropin chloride) in a dose of 1-3
mg/kg after intramuscular and intragastric administration cause maximal analgesic effect in the tail-flick test and formalin test
in 80-100 % of the rats. Dipyridamole inhibiting reuptake of adenosine, in 9-12 times reduces ED50 of adenosine and IEM-1556,
and antagonist of adenosine receptors of 1, 3-dipropyl-8-phenylxanthine (DPX) in 3.8-4.5 times increases ED50 of adenosine and
IEM-1556 in both tests. The obtained results evidences in favor of participation of endogenous adenosine in the mechanism of
the analgesic action IEM-1556. Preliminary anesthesia of the gastric mucosa with 1% lidocaine and subdiaphragmatic gastric
vagotomy almost equally in 3.7-4.4 fold increase ED50 IEM-1556 and adenosine in both tests, indicating the involvement of
vagal afferents in the gastric mucosa in the development of analgesic action both IEM-1556, and adenosine. The coincidence
of the mechanisms of the vagus-stimulating and analgesic action of exogenous adenosine and IEM-1556 demonstrates that
IEM-1556 as a probable liberator of endogenous adenosine after system and oral administration in a low dose of 1-3 mg/kg
causes development of analgesia as a result of stimulation of adenosine-sensitive vagal afferents in gastric mucosa. In higher
doses the analgesic effect of IEM-1556 (which isn’t eliminated by DPX, vagotomy and lidocaine) is presumably explained by
additional blockade of cholinergic nicotinic receptors in the CNS. IEM-1556, which includes the central nicotinic blocking and
peripheral vagus-stimulating components, is the first exemplar of a new class of double-acting analgesics, potentially effective
in the treatment of inflammatory, postoperative and neuropathic pain
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in parasympathetic pathways to the heart in rats. Neurophysiology 27 (5-6), 255—260
2. Tsybenko A, Yanchuk P I, Egorova L S, Gmiro V E (1996) Selective pharmacological blocking of synaptic transmission through
the parasympathetic ganglia: effects on the cardiovascular system.
Neurophysiology
28 (2/3): 119—125.
3. Patent of the Russian Federation No. 2597616, N-alkyl-tropins and N-alkyl-nortropines with n-lytic, antiparkinsonic,
antiepileptic, analgesic and antidepressant activity. Published: 09/10/2016, Byul. The patent holder - Gmiro V.E. Co-authors
- Shabanov P.D., Serdyuk S.E.
4. Gmiro V E and Serdyuk S E (2016) New innovative drug for the treatment of Parkinson's disease, epilepsy and chronic pain,
with a combined n-cholinolitic, adenosine-releasing and vagal-stimulating activity.
The Journal of Pharmaceutics & Drug
Delivery Research,
Vol. 5, Issue 4 (Suppl), P. 81.
5. Gmiro V E, Serdyuk S E (2017) Comparative study of analgesic effect of N-decyltropine (IEM-1556), adenosine and
mecamylamine.
Russian Journal of Physiology
103 (10): 1106-1113 (in Russian)
N-decyltropine (IEM-1556) as the first analgesic with
combined peripheral vagus-stimulating and nicotinic central
blocking effect
V E Gmiro and S E Serdyuk
Institute for Experimental Medicine, St. Petersburg, Russia
V E Gmiro et al., Am J Pharmacol Pharmacother 2018, Volume 5
DOI: 10.21767/2393-8862-C1-003