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.

Antihyperalgesic effects of a novel muscarinic agonist (LASSBio‐873) in spinal nerve ligation in rats

“…In addition, our study provides evidence that the analgesic effect of LASSBio‐873 seems to be mediated through M 2 receptors, reinforcing the recent findings of Mendes et al . in mice . Although a previous study provided evidence for a sedative effect of LASSBio‐873, no effect on locomotor behaviour was observed after oral administration of LASSBio‐873.…”

“…Some authors also demonstrated that activation of supraspinal M 1 receptors is very important for antinociceptive effects of cholinomimetic agents, such as xanomeline and McN‐A343, in neuropathic pain. In the present study, the role of M 1 receptor activation in the action of LASSBio‐873 was not investigated, but we have demonstrated previously the ability of LASSBio‐873 to activate this receptor subtype …”

“…In addition, cholinergic agonists that cross the blood–brain barrier, similar to LASSBio‐873, can activate the ‘cholinergic anti‐inflammatory pathway’ and thereby reduce serum levels of proinflammatory cytokines, such as tumour necrosis factor, which then inhibits the antibody response . Inhibition of the inflammatory pathway ultimately leads to a reduction in neuropathic pain symptoms because it is known to have central effects …”

“…Of the zolpidem derivatives tested, LASSBio‐873 has been shown to be the most effective as an analgesic . The antinociceptive activity of LASSBio‐873 has been shown to be mediated via activation of the muscarinic system and it reduces carrageenan‐induced thermal hyperalgesia as well as formalin‐induced acute inflammatory pain . Unlike the parent compound zolpidem, the pharmacological activities of LASSBio‐873 were not affected by flumazenil (a benzodiazepine receptor antagonist) or yohimbine (an α 2 ‐adrenoceptor antagonist), indicating that muscarinic acetylcholine receptor pathways are selectively important for the drug's analgesic activity …”

Effects of Hypericum montbretti Extract on the Central Nervous System and Involvement of GABA (A)/Benzodiazepine Receptors in its Pharmacological Activity

“…The reference drug Dzm was used at 2 mg/kg in the hole-board (Rao et al, 1999), activity cage (Silva et al, 2011), PTZ-induced seizure (Silva et al, 2011) and Hxbinduced sleeping tests (Silva et al, 2010). Antagonist compounds, including Nlx at 5 mg/kg (Zapata-Sudo et al, 2010), Atr at 2 mg/kg (Mendes et al, 2009) and Flu at 2.5 (Venâncio et al, 2011) and 10 mg/kg (Silva et al, 2011), were administered intraperitoneally 15 min before administration of the extract.…”