Transition of drug reseptor mechanisms.

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It is generally accepted that the agonists, full agonist and partial agonist, interact with the same receptors according to the classical receptor mechanisms. We tried to modify the drug receptor mechanisms in muscarinic cholinoceptors, α1-adrenoceptors and β-adrenoceptors. In the muscarinic cholinoceptor, there are two subtypes of M3-cholinoceptors, propylbenzilylcholine mustard (PrBCM)-sensitive receptors and PrBCM-resistant ones. The full agonists contract the longitudinal muscle through the interaction of two cholinoceptors, PrBCM-sensitive and-resistant ones, while the partial agonists produce the contrac-tion through only the activation of PrBCM-sensitive ones. Upon activation PrBCM-sensi-tive receptors may use cytosolic Ca2+ more effectively than PrBCM-resistant receptors. In the α1-adrenoceptor, the full agonist induces contraction through both ai A and α1B, subtypes and the partial agonist through only α1A, subtype. The adrenoceptors activated by full agonist may be partly different from that by partial agonist in the arteries. In both the common iliac artery and thoracic aorta treated with the irreversible antagonist, phenoxybenzamine the slopes of schild plots of the results obtained from an antagonism between full agonist (phenylephrine) and α1A-selective competitive antagonist (WB4101) equal to 1, suggesting that phenoxybenzamine preferably interacts with α1B, subtype. In the β-adrenoceptor, the pD2-values of the partial agonists obtained from the concentration-response curves are significantly different from their pA2-values against full agonist (isoprenaline). The Scatchard plot of the specific [3H] befunolol (the partial agonist) binding showed two affinity sites of the receptors in the absence of Gpp (NH) p but the low affinity site was reduced while the high affinity site was not affected in the presence of Gpp (NH) p.The β-adrenergic partial agonists are able to discriminate these two different binding sites of the β-adrenoceptors. Our results suggest that the receptors activated by full agonists are partly different from those by partial agonists in muscarinic cholinoceptors, α1-and β-adrenoceptors, and that the irreversible antagonist can discriminate between the sites interact with full agonists and those with partial agonists in muscarinic cholinoceptors and α1-adrenoceptors.
日本平滑筋学会の論文

Transition of drug reseptor mechanisms.

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