IDAVERINE, AN M2-SELECTIVE VS M3-SELECTIVE MUSCARINIC ANTAGONIST, DOES NOT PREVENT MOTION SICKNESS IN CATS

In this study, the affinity profile of idaverine for the M1- (neuronal tissue), M2- (heart) and M3- (glandular tissue/nonvascular smooth muscle) muscarinic receptors was examined by means of radioligand binding and in vitro organ bath experiments in order to use the compound for the investigation of the muscarinic receptor subtype involved in motion sickness. In the profile study a comparison was made with the muscarinic antagonists atropine, pirenzepine (M1-selective) AF-DX 116 (M2-selective) and 4-DAMP (high affinity for M1- and M3-binding sites). The affinity of idaverine appeared to be equally high for the M1- and M2-binding sites. However, the affinity for the M1-binding sites should be interpreted cautiously since the Hill slope deviated from unity. Idaverine showed a 20-fold selectivity for the M2-binding sites over the M3-binding sites, whereas it showed a small selectivity (< 5-fold) for the M2-receptors compared to the ileal and tracheal smooth muscle receptors. Thus idaverine appears to be M2 over M3 selective. However, in contrast to AF-DX 116, it is not clear whether idaverine is also M2 over M1 selective. In experiments with cats, idaverine failed to prevent motion sickness at doses from 0.03 to 3 mg/kg. These results are interpreted to implicate M3-receptors in the motion sickness suppressant effect of antimuscarinic drugs.