Glutamine 57 at the complementary binding site face is a key determinant of morantel selectivity for Ą7 nicotinic receptors

M BARTOS,; PRICE KERRY; LUMMIS S; C BOUZAT

JOURNAL OF BIOLOGICAL CHEMISTRY

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Año: 2009 vol. 284 p. 21478 - 21487

0021-9258

Nicotinic receptors (AChRs) play key roles in synaptic transmission. We explored activation of neuronal 7 and mammalian muscle AChRs by morantel and oxantel. Our results revealed a novel action of morantel as a high efficacy and more potent agonist than ACh of 7 receptors. The EC50 for activation by morantel of both 7 and 7-5HT3A receptors is 7-fold lower than that determined for ACh. The minimum morantel concentration required to activate 7-5HT3A channels is 6-fold lower than that of ACh, and activation episodes are more prolonged than in the presence of ACh. By contrast, oxantel is a weak agonist of 7 and 7-5HT3A, and both drugs are very low efficacy agonists of muscle AChRs. The replacement of Gln57 in7 and mammalian muscle AChRs by morantel and oxantel. Our results revealed a novel action of morantel as a high efficacy and more potent agonist than ACh of 7 receptors. The EC50 for activation by morantel of both 7 and 7-5HT3A receptors is 7-fold lower than that determined for ACh. The minimum morantel concentration required to activate 7-5HT3A channels is 6-fold lower than that of ACh, and activation episodes are more prolonged than in the presence of ACh. By contrast, oxantel is a weak agonist of 7 and 7-5HT3A, and both drugs are very low efficacy agonists of muscle AChRs. The replacement of Gln57 in7 receptors. The EC50 for activation by morantel of both 7 and 7-5HT3A receptors is 7-fold lower than that determined for ACh. The minimum morantel concentration required to activate 7-5HT3A channels is 6-fold lower than that of ACh, and activation episodes are more prolonged than in the presence of ACh. By contrast, oxantel is a weak agonist of 7 and 7-5HT3A, and both drugs are very low efficacy agonists of muscle AChRs. The replacement of Gln57 in7 and 7-5HT3A receptors is 7-fold lower than that determined for ACh. The minimum morantel concentration required to activate 7-5HT3A channels is 6-fold lower than that of ACh, and activation episodes are more prolonged than in the presence of ACh. By contrast, oxantel is a weak agonist of 7 and 7-5HT3A, and both drugs are very low efficacy agonists of muscle AChRs. The replacement of Gln57 in7-5HT3A channels is 6-fold lower than that of ACh, and activation episodes are more prolonged than in the presence of ACh. By contrast, oxantel is a weak agonist of 7 and 7-5HT3A, and both drugs are very low efficacy agonists of muscle AChRs. The replacement of Gln57 in7 and 7-5HT3A, and both drugs are very low efficacy agonists of muscle AChRs. The replacement of Gln57 in57 in 7 by glycine, which is found in the equivalent position of the muscle AChR, decreases the efficacy for activation and turns morantel into a partial agonist. The reverse mutation in the muscle AChR (G57Q) increases 7-fold the efficacy of morantel. The mutations do not affect activation by ACh or oxantel, indicating that this position is selective for morantel. In silico studies show that the tetrahydropyrimidinyl group, common to both drugs, is close to Trp149 of the principal face of the binding site, whereas the other cyclic group is proximal to Gln57 of the complementary face in morantel but not in oxantel. Thus, position 57 at the complementary face is a key determinant of the high selectivity of morantel for 7. These results provide new information for further progress in drug design.7 by glycine, which is found in the equivalent position of the muscle AChR, decreases the efficacy for activation and turns morantel into a partial agonist. The reverse mutation in the muscle AChR (G57Q) increases 7-fold the efficacy of morantel. The mutations do not affect activation by ACh or oxantel, indicating that this position is selective for morantel. In silico studies show that the tetrahydropyrimidinyl group, common to both drugs, is close to Trp149 of the principal face of the binding site, whereas the other cyclic group is proximal to Gln57 of the complementary face in morantel but not in oxantel. Thus, position 57 at the complementary face is a key determinant of the high selectivity of morantel for 7. These results provide new information for further progress in drug design.In silico studies show that the tetrahydropyrimidinyl group, common to both drugs, is close to Trp149 of the principal face of the binding site, whereas the other cyclic group is proximal to Gln57 of the complementary face in morantel but not in oxantel. Thus, position 57 at the complementary face is a key determinant of the high selectivity of morantel for 7. These results provide new information for further progress in drug design.149 of the principal face of the binding site, whereas the other cyclic group is proximal to Gln57 of the complementary face in morantel but not in oxantel. Thus, position 57 at the complementary face is a key determinant of the high selectivity of morantel for 7. These results provide new information for further progress in drug design.57 of the complementary face in morantel but not in oxantel. Thus, position 57 at the complementary face is a key determinant of the high selectivity of morantel for 7. These results provide new information for further progress in drug design.7. These results provide new information for further progress in drug design.