Phencyclidine metabolism: resolution, structure, and biological activity of the isomers of the hydroxymetabolite, 4-phenyl-4-(1-piperidinyl)cyclohexanol

Abstract

One of the major biotransformation pathways in the metabolism of phencyclidine is hydroxylation at C-4 of the cyclohexane ring to give 4-phenyl-4-(1-piperidinyl)cyclohexanol (1). Since the latter compound can exist as cis and trans isomers and the synthetic mixture has been reported to be biologically active, it was of interest to separate the isomers, test them for biological activity, and determine their ratio as metabolic products of phencyclidine. The synthetic mixture of 1 was separated by TLC and the individual isomers were characterized by 13C and 1H NMR and MS analyses. Preliminary testing of the isomers in the mouse rotarod assay indicates that the trans isomer (1b) is only slightly more active then the cis isomer (1a). Both isomers produced seizure activity and lethality at doses required to produce maximal ataxia.

Metabolic-Hydroxy and Carboxy Functionalization of Alkyl Moieties in Drug Molecules: Prediction of Structure Influence and Pharmacologic Activity

“…An interesting case of metabolic hydroxylation of alicycles and aliphatic heterocycles is given by the psychotropic drug phencyclidine, which contains both cyclohexyl and piperidinyl groups. Phencyclidine is mainly metabolized by hydroxylation at position 4 of the cyclohexyl ring to the active cisand trans-4-phenyl-4-(1-piperidinyl)cyclohexanol (Figure 35) [115]. In addition, the piperidinyl ring in phencyclidine is metabolically hydroxylated to a minor extent at position 4 to give 4-phenyl-4-(1-coclohexyl)piperidinyl alcohol [116].…”

“…A tentative inference can be made heeding the phencyclidine metabolic hydroxylation example: when an alicycle and aliphatic heterocycle are parts of the same molecule, metabolic hydroxylation favors the alicycle over the heterocycle. active cis-and trans-4-phenyl-4-(1-piperidinyl)cyclohexanol (Figure 35) [115]. In addition, the piperidinyl ring in phencyclidine is metabolically hydroxylated to a minor extent at position 4 to give 4-phenyl-4-(1-coclohexyl)piperidinyl alcohol [116].…”

Clinical Pharmacokinetics of Non-Opiate Abused Drugs

“…Following intravenous PCP administration under uncontrolled urinary pH, 19.4% of the excreted fraction in urine is composed of non-polar compounds (mainly unchanged drug), while 80.6% of the excreted fraction contains polar metabolites [mainly 4-phenyl-4-(1-piperidinyl) cyclohexanol]. The latter has been shown to have some pharmacological activity (Carroll et al 1981).…”

Uridine 5'-diphosphate glucose analogs. Inhibitors of protein glycosylation that show antiviral activity

“…Reaction of 2,3,4,6-Tetra-O-benzyl-a-D-glucopyranose (7) with Chlorosulfonyl Isocyanate ( 8) and 2',3'-0-Isopropylideneuridine (11). A solution of 7 (3.24 g, 6 mmol) in dry methylene chloride (30 mL) cooled at -20 to -15 °C was treated in the absence of humidity with chlorosulfonyl isocyanate (0.52 mL, 6 mmol).…”

“…0022-2623 / 85/1828-0040$01.50/0 Reaction of 2,3,4,6-tetra-O-benzyl-a-D-glucopyranose (7) with chlorosulfonyl isocyanate (8) in methylene chloride at low temperature and with exclusion of moisture afforded the unstable [ [ [ (chlorosulfonyl) amino] carbonyl] oxy]glucose 9, which, by in situ reaction with 2',3/-Q-isopropyIideneuridine gave 5'-0-[[[[(2",3//,4",6"-tetra-0-benzyl-a-Dglucopyranosyl)oxy]carbonyl] amino] sulfonyl]-2/,3,-0-isopropylideneuridine (13) in 40% yield (Scheme I). Compound 9 was formed by reaction of the isocyanate group, more reactive toward nucleophiles than the chlorosulfonyl group of 8,13 with the glucose anomeric hydroxyl group.…”