Thiochrome enhances acetylcholine affinity at muscarinic M4 receptors: receptor subtype selectivity via cooperativity rather than affinity.

Thiochrome (2,7-dimethyl-5H-thiachromine-8-ethanol), an oxidation product and metabolite of thiamine, has little effect on the equilibrium binding of l-[3H]N-methyl scopolamine ([3H]NMS) to the five human muscarinic receptor subtypes (M1-M5) at concentrations up to 0.3 mM. In contrast, it inhibits [3H]NMS dissociation from M1 to M4 receptors at submillimolar concentrations and from M5 receptors at 1 mM.

Progress toward a high-affinity allosteric enhancer at muscarinic M1 receptors.

Loss of forebrain acetylcholine is an early neurochemical lesion in Alzheimer's disease (AD). As muscarinic acetylcholine receptors are involved in memory and cognition, a muscarinic agonist could therefore provide a "replacement therapy" in this disease. However, muscarinic receptors occur throughout the CNS and the periphery.

Analogs of WIN 62,577 define a second allosteric site on muscarinic receptors.

WIN 51,708 (17-beta-hydroxy-17-alpha-ethynyl-5-alpha-androstano[3,2-b]pyrimido[1,2-a]benzimidazole) and WIN 62,577 (17-beta-hydroxy- 17-alpha-ethynyl-delta(4)-androstano[3,2-b]pyrimido[1,2-a]benzimidazole) are potent and centrally active antagonists at rat, but not human, NK(1) receptors. The interactions of these compounds and some analogs with [(3)H]N-methyl scopolamine ([(3)H]NMS) and unlabeled acetylcholine (ACh) at M(1)-M(4) muscarinic receptors have been studied using equilibrium and nonequilibrium radioligand binding methods. The results are consistent with the predictions of the allosteric ternary complex model.

Towards a high-affinity allosteric enhancer at muscarinic M1 receptors.

Loss of forebrain acetylcholine (ACh) is an early neurochemical lesion in Alzheimer's Disease (AD), and muscarinic receptors for ACh are involved in memory and cognition, so a muscarinic agonist could provide 'replacement therapy' in this disease. Muscarinic receptors, which couple to G-proteins, occur throughout the CNS, and in the periphery they mediate the responses of the parasympathetic nervous system, so selectivity is crucial. The five subtypes of muscarinic receptor, M1-M5, have a distinct regional distribution, with M2 and M3 mediating most of the peripheral effects, M2 predominating in hindbrain areas, and M1 predominating in the cortex and hippocampus--the brain regions most associated with memory and cognition, which has lead to a search for a truly M1-selective muscarinic agonist.

Substituted pentacyclic carbazolones as novel muscarinic allosteric agents: synthesis and structure-affinity and cooperativity relationships.

Two series of pentacyclic carbazolones, 22 and 23, have been synthesized utilizing a facile intramolecular Dielsminus signAlder reaction and are allosteric modulators at muscarinic acetylcholine receptors. Their affinities and cooperativities with acetylcholine and the antagonist N-methylscopolamine (NMS) at M(1)minus signM(4) receptors have been analyzed and compared. All of the synthesized compounds are negatively cooperative with acetylcholine.