[Pharmacological studies on drug receptor mechanisms]

During the past ten years, the experiments based on the following three main propositions were carried out in our laboratory. (1) Drug receptor mechanisms. M3-Cholinoceptors and alpha 1-adrenoceptors could be divided into two subtypes which were discriminated by beta-chloroethylamines only in the presence of GTP. The full agonists interacted with both subtypes to induce responses. The partial agonists activated one of them to induce responses but behaved as competitive antagonists when they interacted with the other. The responses mediated through the receptors which were activated by the partial agonists were resistant to myosin light chain kinase inhibitors, while the responses by the activation of the other receptors were suppressed by the inhibitors. The possible mechanisms for responses mediated through alpha 1-adrenoceptors and M3-cholinoceptors were discussed. beta-Adrenoceptors had also two binding sites, high and low affinity sites, which could be discriminated by the partial agonists. (2) Effects of ageing on drug receptor mechanisms. Potencies of alpha- and beta-adrenoceptor agonists increased from the young stage to the adult stage and decreased slowly thereafter to the old stage. The affinities of adrenergic drugs for their receptors did not alter with ageing. The changes in the adrenoceptor-mechanisms with ageing were mainly due to the changes in the amount of receptors. However, the decrease in the potency of beta-agonists in the preparations from the older animals was due to the change in the post beta-receptor processes in responsiveness. No age-related change was observed in serotonin, acetylcholine and tachykinin receptor mechanisms. However, the potencies of acetlcholine and tachykinin were modified by the change in the activity of related enzymes, which altered with ageing. (3) Drug design. Taking into account pharmacological studies on opioid receptors, N-cyclopropylmethyl normorphine derivatives were synthesized. They had more potent analgesic action than morphine through the activation of kappa-opioid receptors. They might not possess dependence liability.