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Sedation and antinociception induced by a new pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivative (LASSBio-873) is modulated by activation of muscarinic receptors.

Abstract
New substances designed for the treatment of anxiety have previously been synthesized, which resulted in the identification of four new pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivatives structurally designed by using zolpidem as lead compound. Among them, LASSBio-873 was the most potent to produce analgesic, sedative and hypnotic effects. Thus, we investigated the possible mechanisms involved in LASSBio-873-induced sedation, as well as its effects on different models of inflammatory pain. LASSBio-873 (4 mg/kg) reduced locomotor activity of mice in the open field test from 205.2+/-25.6 to 87.6+/-16.2 movements/min. Atropine, a non-selective muscarinic antagonist, prevented the LASSBio-873-induced sedation and increased locomotor activity to 192.9+/-30.2 movements/min. In the formalin test, LASSBio-873 (4 mg/kg) significantly reduced the duration of nociceptive behavior during the inflammatory phase, reducing the control reactivity from 197.6+/-14.5s to 84.4+/-10.3s. Carrageenan reduced the latency for the animal reaction from 5.1+/-0.2s (control) to 2.1+/-0.3s which was completely reverted by LASSBio-873 (6 mg/kg) to 5.6+/-0.6s. Atropine prevented the LASSBio-873-induced antinociceptive and antihyperalgesic activities, indicating the interference of the cholinergic system. LASSBio-873 is a novel prototype of drug that modulates muscarinic activity and could be used for neuropsychiatric and cognitive disorders and other conditions associated to acute and chronic pain.
AuthorsThaiana C F Mendes, Juliana M Raimundo, Nailton M Nascimento-Junior, Carlos A M Fraga, Eliezer J Barreiro, Roberto T Sudo, Gisele Zapata-Sudo
JournalPharmacology, biochemistry, and behavior (Pharmacol Biochem Behav) Vol. 94 Issue 1 Pg. 70-4 (Nov 2009) ISSN: 1873-5177 [Electronic] United States
PMID19635495 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Adrenergic alpha-Antagonists
  • Analgesics
  • GABA Antagonists
  • Hypnotics and Sedatives
  • LASSBio-873
  • Muscarinic Antagonists
  • Narcotic Antagonists
  • Pyrazoles
  • Pyridines
  • Pyrroles
  • Receptors, Muscarinic
Topics
  • Adrenergic alpha-Antagonists (metabolism)
  • Analgesics (administration & dosage, pharmacology)
  • Analysis of Variance
  • Animals
  • Behavior, Animal (drug effects)
  • Dose-Response Relationship, Drug
  • Exploratory Behavior (drug effects)
  • GABA Antagonists (metabolism)
  • Hot Temperature
  • Hyperalgesia (drug therapy)
  • Hypnotics and Sedatives (administration & dosage, pharmacology)
  • Inflammation (chemically induced, physiopathology)
  • Male
  • Mice
  • Motor Activity (drug effects)
  • Muscarinic Antagonists (metabolism)
  • Narcotic Antagonists (metabolism)
  • Pain (drug therapy)
  • Pain Measurement
  • Pyrazoles (administration & dosage, pharmacology)
  • Pyridines (administration & dosage, pharmacology)
  • Pyrroles (administration & dosage, pharmacology)
  • Receptors, Muscarinic (metabolism)

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