12+

ANTI-INFLAMMATORY AND ANALGESIC PROPERTIES OF SS-68 INDOLE DERIVATIVE

The experiments with rats show that when administered intravenously (5 mg/kg) and intragastrically (5, 10, 15 and 20 mg/kg), SS-68 compound exerts an anti-inflammatory effect (AIE) on models of acute inflammation, caused by carrageenin and serotonin, and exerts no AIE in case of edema induced by complete Freund’s adjuvant (CFA) and histamine, except for intragastric administration at a dose of 20 mg/kg.

By its antiphlogogenic effect in case of carrageenin and serotonin edemas, SS-68 is comparable to diclofenac (5, 10 and 15 mg/kg intragastrically) and indomethacin (10 mg kg intragastriccally), and exceeds piroxicam (20 mg/kg intragastrically). By reference to its therapeutic index (TI), in the first case SS-68 exceeds diclofenac, indomethacin and piroxicam 2.2, 15.6 and 5.6 times, and in the second case it exceeds them 1.8, 12.8 and 4.4 times, respectively.

In the mouse acetic writhing test, which reflects the predominant effect on κ (kappa)-opioid receptors, SS-68 when administered intraperitoneally at doses of 0.03, 0.06 and 0.12 mg/kg causes a dose-dependent decrease in the number of writhes by 40.0, 69.0 and 80.3%, respectively.   Butorphanol, used for comparison in doses of 0.03, 0.12, 0.24, 0.48 and 0.96 mg/kg, exerts a dose-dependent analgesic effect (AE), with the number of writhes being 41.5, 52.4, 65.3, 71.1 and 80.6%, respectively. By its analgesic activity and TI, SS-68 exceeds butorphanol 1.9 and 2.7 times, respectively.

Based on the results of the docking of affinity indicators for κ1-opioid receptors of SS-68, butorphanol (agonist-antagonist), as well as U-50488 compounds (selective agonist), it was established that, in accordance with the calculated values of the binding constant, the affinity in relation to SS-68 was 4.53 times higher than for butorphanol, and when compared with U-50488 it was 2.84 times lower. The suggestion is that AE of SS-68, like that of butorphanol, can be linked with both affinity for κ1-receptors and for other types of opioid receptors (mu, delta) and κ-receptor subtypes (κ2 or κ3).

Иллюстрации

where I is an increase in paw volume (%); Vt - paw volume after injection of phlogogen (ml); and Vo - paw volume before phlogogone administration (ml).

where (e) are experimental animals, (c) are control animals.

where Nк is the number of writhes in the control group of animals, N – in the experimental group.

where R is gas constant equal to 8.314 J/mol; T – temperature, the standard value in docking is 300 oK.

Table 1  The impact of SS-68, diclofenac, indomethacin and piroxicam on the development of acute exudative edema caused by carrageenin, CFA, serotonin and histamine in rats (M ± m)

Table 2. Acute toxicity, anti-inflammatory effect and TI of SS-68, on carrageenan and

 serotonin models of exudative inflammation in rats

Table 3. Analgesic effect of SS-68 and butorphanol with ip administration in mouse acetic writhing test (M ± m)

Table 4. Acute toxicity, analgesic effect and TI of SS-68 and butorphanol when administered ip in mouse acetic writhing test

Table 5. Results of docking SS-68, butorphanol and U-50488 substance into specific binding site of κ1-opioid receptor

DOI: 10.18413/2313-8971-2017-3-4-26-34
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