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5-Amino-1-methylquinolinium (5-Amino-1MQ) is a small-molecule inhibitor of nicotinamide N-methyltransferase (NNMT), the cytosolic enzyme that methylates nicotinamide to 1-methylnicotinamide (1-MNA) using S-adenosyl-L-methionine (SAM) as the methyl donor

2021, Brescoll, Jennifer, and Steven Daveluy

AOD-9604 Pharmacokinetics & Metabolism Absorption & Distribution AOD-9604 exhibits unusual pharmacokinetic properties for a peptide, demonstrating activity via multiple administration routes in preclinical models: Oral bioavailability confirmed in pig and rodent studies, an uncommon characteristic for peptide compounds Rapid systemic distribution following intraperitoneal administration in mice (15-30 minutes) Following IV administration in pigs, AOD-9604 and degradation fragments appeared rapidly in plasma Oral administration showed slower kinetics but similar degradation product profiles Distribution studies using radiolabeled peptide (C-14-AOD9604) in rats revealed: Elevated concentrations in pineal body and thyroid tissues Distribution to all non-CNS tissues examined Minimal penetration of blood-brain barrier Tissue-specific accumulation patterns suggesting potential targeting mechanisms Metabolism & Elimination The metabolic fate of AOD-9604 involves rapid degradation through sequential N-terminal amino acid removal,: Plasma half-life of approximately 3 minutes following IV administration in pigs (compared to 21 minutes for full-length growth hormone) Sequential amino-terminal truncation represents the primary degradation pathway Principal metabolites identified in vivo include -2 amino acid and -3 amino acid fragments These truncated fragments retain some reduced in vitro anti-lipogenic activity A significant pharmacokinetic paradox exists: despite rapid plasma clearance (peptide undetectable at 56 minutes in spiked plasma studies), biological effects on body weight and fat metabolism persist for hours to days

Researchers confirmed this through knockout studies in mice, where animals lacking beta-3 adrenergic receptors showed zero response to AOD 9604, proving the peptide works specifically through this receptor pathway in adipose tissue