Multiple species metabolism of PHA-568487, a selective alpha 7 nicotinic acetylcholine receptor agonist

Drug Metab Lett. 2010 Aug;4(3):162-72.


The quinuclidine PHA-0568487(1) is an agonist of the alpha 7 nicotinic acetylcholine receptor that was designed to mitigate the bioactivation associated with the core scaffold and subsequently remove associated liabilities with in vivo tolerability. The drug metabolites of 1 in nonclinical species were identified in plasma and urine of rats, dogs and monkeys receiving oral administrations of 1. The in vitro biotransformation of 1 was subsequently investigated in multiple species employing cryopreserved hepatocytes, hepatic subcellular fractions and recombinantly-expressed human P450 enzymes. In addition, in vitro metabolism of synthetically prepared metabolite precursors were instrumental in the elucidation of several secondary metabolites. The results indicated that the principal biotransformation of 1 was oxidation of the benzo[1,4]dioxane moiety (M8, M10) followed by subsequent oxidation to a range of secondary metabolites (M1-7, M9, M11, M13-15, and M17-18). The carboxylic acids M1 and M2 resulting from the oxidative cleavage of the dioxane ring were the principal metabolites observed in the plasma, urine and hepatocyte incubations across all species (M1 & M2). Quinuclidine oxidation was another pathway of importance, yielding an N-oxide (M12) which was also observed in all species.P450 2D6 and FMO1 catalyze the oxidation of the quinuclidine nitrogen. The N oxidation of the quinuclidine moiety is consistent with previously published accounts of this scaffold's metabolism and, interestingly, may implicate the uncommon quinuclidine moiety as an entity directing the metabolism of this scaffold (e.g., 1) via FMO1 and P450 2D6 oxidation.

MeSH terms

  • Administration, Oral
  • Animals
  • Aza Compounds / administration & dosage
  • Aza Compounds / blood
  • Aza Compounds / pharmacokinetics*
  • Aza Compounds / urine
  • Biotransformation
  • Chromatography, Liquid
  • Cytochrome P-450 CYP2D6 / metabolism
  • Dioxins / administration & dosage
  • Dioxins / blood
  • Dioxins / pharmacokinetics*
  • Dioxins / urine
  • Dogs
  • Haplorhini
  • Hepatocytes / enzymology
  • Humans
  • Magnetic Resonance Spectroscopy
  • Nicotinic Agonists / administration & dosage
  • Nicotinic Agonists / blood
  • Nicotinic Agonists / pharmacokinetics*
  • Nicotinic Agonists / urine
  • Oxidation-Reduction
  • Oxygenases / metabolism
  • Quinuclidines / administration & dosage
  • Quinuclidines / blood
  • Quinuclidines / pharmacokinetics*
  • Quinuclidines / urine
  • Rats
  • Receptors, Nicotinic / drug effects*
  • Recombinant Proteins / metabolism
  • Tandem Mass Spectrometry
  • alpha7 Nicotinic Acetylcholine Receptor


  • Aza Compounds
  • Chrna7 protein, human
  • Chrna7 protein, rat
  • Dioxins
  • Nicotinic Agonists
  • PHA-568487E
  • Quinuclidines
  • Receptors, Nicotinic
  • Recombinant Proteins
  • alpha7 Nicotinic Acetylcholine Receptor
  • Oxygenases
  • dimethylaniline monooxygenase (N-oxide forming)
  • Cytochrome P-450 CYP2D6