Neurotransmitter Receptors and Their Ionic Channels as Targets for Drugs and Toxins
Final rept. 28 Sep 1981-9 Sep 1984
MARYLAND UNIV BALTIMORE SCHOOL OF MEDICINE
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A variety of drugs inhibited nicotinic acetylcholine ACh receptor function competitively via its agonist-binding site andor noncompetitively via its allosteric sites. Drugs acting on the latter sites included amantadine and perhydrohistrionicotoxin, which bound to the open and closed channel conformation, such as physostigmine, scopdlamine, gephyrotoxin, bupivacaine, while other drugs, such as meproadiifen and imipramine, blocked the closed and intermediate nonconducting channel conformation. While m-amino-PCP blocked only the closed and intermediate nonconducting conformations, m-nitro-PCP blocked the open channel conformation as well. There was excellent correlation between the potencies of a series of aliphatic alcohols in simulating 3H perhydrohistrionucotoxin binding to the receptors channnel sites and their membranebuffer partition coefficients. Pyrethriods acted like alcohols and both inhibited binding to the activated receptor conformation. The alcohol moiety of the pyrethroid was more important for these effects than the acidic moiety. Several drugs enhanced receptor desensitization, such as gephyrotoxin and meproadifen. Receptor desensitization was dependent upon temperature.