Interaction of a new potent anticholinesterasic compound (+/-)huprine X with muscarinic receptors in rat brain.
The interaction of rac-12-amine-3-clor-6,7,10,11-tetrahydro-9-ethyl-7-11-methanecyclo-octane[b]quinoline ((+/-)huprine X) with M(1) and M(2) receptors has been studied in rat brain. Specific binding of [(3)H]pirenzepine or [(3)H]quinuclinidylbenzylate to hippocampus preparations was inhibited by (+/-)huprine X. This drug displayed a greater affinity for M(1) (K(i)=0.338+/-0.41 microM) than M(2) (K(i)=4.66+/-0.32 microM) receptors. In functional studies, (+/-)huprine X (1 microM) increased the release of [(3)H]dopamine in cortical synaptosomes, and this effect was partially reverted by atropine and mecamylamine, suggesting an agonistic effect on both M(1) and nicotinic receptors. The inhibitory effect of (+/-)huprine X (10 microM) on [(3)H]acetylcholine release and the subsequent reversion by atropine suggests that the drug also has an agonist effect on M(2) receptors. The present results demonstrate that this acetylcholinesterase inhibitor has an ample cholinergic profile, which suggests a potential source of interest of (+/-)huprine X in Alzheimer's disease therapy.
Roman
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Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
Vivas
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NM
Badia
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A
Clos
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MV
D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000378:metabolism; D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006624:Hippocampus / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000378:metabolism / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010890:Pirenzepine / Q000378:metabolism; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D000634:Aminoquinolines; D002800:Cholinesterase Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D018727:Muscarinic Antagonists; D018733:Nicotinic Antagonists; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; C404518:huprine X; D010890:Pirenzepine; D011813:Quinuclidinyl Benzilate; D008464:Mecamylamine; D001285:Atropine; D000109:Acetylcholine; D004298:Dopamine