N-(3-Iodophenyl)trozamicol (IPHT) and related inhibitors of vesicular acetylcholine transport: synthesis and preliminary biological characterization.

Four isomeric N-(halophenyl)trozamicol analogues (6a-d) were synthesized and evaluated as potential vesicular acetylcholine transporter (VAChT) ligands. Of the four compounds, N-(3-bromophenyl) trozamicol (6b) and N-(3-iodophenyl)trozamicol (6d) displayed the highest affinity for the VAChT in vitro, whereas the para-substituted compound 6c showed the lowest affinity for this transporter. Tissue distribution studies of N-(3-[125I]iodophenyl)trozamicol ([125I]6d, [125I)IPHT) suggest that the central distribution of the latter is consistent with cholinergic innervation.

M1, M3 and M5 muscarinic receptors stimulate mitogen-activated protein kinase.

We report here that the M1, M3 and M5 muscarinic acetylcholine receptor subtypes that have been shown to couple to phosphoinositide hydrolysis also activate the mitogen-activated protein kinase (MAPK). Pharmacological characterization as well as mechanistic details of the activation pathway are presented. Carbachol-induced MAPK activation was time- and concentration-dependent at all subtypes.

Measurement of functional cholinergic innervation in rat heart with a novel vesamicol receptor ligand.

Regional differences in cholinergic activity in the cardiac conduction system have been difficult to study. We tested the utility of (+)-m-[125I]iodobenzyl)trozamicol(+)-[125I]MIBT), a novel radioligand that binds to the vesamicol receptor located on the synaptic vesicle in presynaptic cholinergic neurons, as a functional marker of cholinergic activity in the conduction system. The (+)-[125I]MIBT was injected intravenously into four rats.

Age-related diminution of dopamine antagonist-stimulated vesamicol receptor binding.

Unlabelled: Previous studies of radiolabeled vesamicol receptor (VR) ligands suggest that the latter may be used in conjunction with dopamine D2 antagonists to measure changes in striatal cholinergic function. In this study, the effects of aging on vesicular acetylcholine storage/release were investigated with the high-affinity VR ligand (+)-meta-[125I)iodobenzyltrozamicol [(+)-[125I]MIBT].

Methods: Male Fischer 344 rats (aged 3 and 24 mo) were injected either with a vehicle or a D2 antagonist [haloperidol or S-(-)-eticlopride].

The vesamicol receptor ligand (+)-meta-[125I]iodobenzyltrozamicol [(+)-[125I]-MIBT] reveals blunting of the striatal cholinergic response to dopamine D2 receptor blockade in the 6-hydroxydopamine (6-OHDA)-lesioned rat: possible implications for Parkinson's disease.

Previous studies of radiolabelled vesamicol receptor (VR) ligands suggest that the latter may be used, in conjunction with dopamine D2 antagonists, to measure changes in striatal cholinergic function in vivo. In the present study, the radiolabelled VR ligand (+)-meta-[125I]iodobenzyltrozamicol {(+)-[125I]MIBT} was used to assess striatal cholinergic function in the unilateral 6-hydroxydopamine (6-OHDA)-treated rat. In control animals, the levels of this radiotracer monitored at 3 hr post injection displayed bilateral symmetry in the striatum, cerebral cortex and cerebellum.