Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists

Biased agonism at G protein–coupled receptors describes the phenomenon whereby some drugs can activate some downstream signaling activities to the relative exclusion of others. Descriptions of biased agonism focusing on the differential engagement of G proteins versus β-arrestins are commonly limited by the small response windows obtained in pathways that are not amplified or are less effectively coupled to receptor engagement, such as β-arrestin recruitment. At the μ-opioid receptor (MOR), G protein–biased ligands have been proposed to induce less constipation and respiratory depressant side effects than opioids commonly used to treat pain. However, it is unclear whether these improved safety profiles are due to a reduction in β-arrestin–mediated signaling or, alternatively, to their low intrinsic efficacy in all signaling pathways. Here, we systematically evaluated the most recent and promising MOR-biased ligands and assessed their pharmacological profile against existing opioid analgesics in assays not confounded by limited signal windows. We found that oliceridine, PZM21, and SR-17018 had low intrinsic efficacy. We also demonstrated a strong correlation between measures of efficacy for receptor activation, G protein coupling, and β-arrestin recruitment for all tested ligands. By measuring the antinociceptive and respiratory depressant effects of these ligands, we showed that the low intrinsic efficacy of opioid ligands can explain an improved side effect profile. Our results suggest a possible alternative mechanism underlying the improved therapeutic windows described for new opioid ligands, which should be taken into account for future descriptions of ligand action at this important therapeutic target.

STUDY OF POTENTIAL ANTITUSSIVE ACTIVITY OF GLYCYRRHIZA GLABRA GRANULES BY USING A COUGH MODEL INDUCED BY SULPHUR DIOXIDE GAS IN MICE

In respiratory diseases cough is most common symptom. When cough becomes severe, opioids are potent, but they have side effects like sedation, constipation. Therefore, there is a necessary to have effective antitussive formulation, which does not have respiratory depressant activity. The present study was carried out to analysis antitussive activity of Glycyrrhiza glabra L. using a cough model induced by sulphur dioxide gas in experimental mice. The effect of the granules of Glycyrrhiza glabra extract on SO2 gas induced cough in experimental animals have very significant effects at the level of p<0.01 in inhibiting the cough reflex at a dose of 200 mg/kg body weight, in comparison with the control group. Mice were showed an inhibition of 41.17%, in cough on treatment with Glycyrrhiza glabra granules at 60 min experiment. The antitussive activity of the granules was comparable to that of codeine sulphate (10, 15, 20 mg/kg body weight), a standard anti-tussive agent. Codeine sulphate, as a standard drug for suppression of cough, produced 25.29%, 33.33%, 47.13% inhibition in cough at a dose of 10 mg/kg, 15 mg/kg and 20 mg/kg respectively, whereas, codeine sulphate (20 mg/kg) showed maximum 47.13% (p<0.001) inhibition at 60 min of the experiment.