TBPB is a bitopic ligand, interacting with both the orthosteric site and an allosteric site, at the M₁ mAChR. TBPB activates M(1) through an allosteric site rather than the orthosteric acetylcholine binding site, which is likely critical for its unprecedented selectivity. Whole-cell patch-clamp recordings demonstrated that activation of M(1) by TBPB potentiates NMDA receptor currents in hippocampal pyramidal cells but does not alter excitatory or inhibitory synaptic transmission, responses thought to be mediated by M(2) and M(4). TBPB was efficacious in models predictive of antipsychotic-like activity in rats at doses that did not produce catalepsy or peripheral adverse effects of other mAChR agonists. Finally, TBPB had effects on the processing of the amyloid precursor protein toward the non-amyloidogenic pathway and decreased Abeta production in vitro.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 20 mg/mL|
tert-Butyl peroxybenzoate (TBPB)-mediated 2-isocyanobiaryl insertion with 1,4-dioxane: efficient synthesis of 6-alkyl phenanthridines via C(sp3)-H/C(sp2)-H bond functionalization.
Cao JJ, et al. Chem Commun (Camb). 2014 Jun 21;50(49):6439-42. PMID: 24699898.
Reverse engineering of the selective agonist TBPB unveils both orthosteric and allosteric modes of action at the M₁ muscarinic acetylcholine receptor.
Keov P, et al. Mol Pharmacol. 2013 Sep;84(3):425-37. PMID: 23798605.
Novel selective allosteric activator of the M1 muscarinic acetylcholine receptor regulates amyloid processing and produces antipsychotic-like activity in rats.
Jones CK, et al. J Neurosci. 2008 Oct 8;28(41):10422-33. PMID: 18842902.
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