Synthesis and pharmacology of a series of 3- and 4-(phosphonoalkyl)pyridine- and -piperidine-2-carboxylic acids. Potent N-methyl-D-aspartate receptor antagonists

Abstract

We recently prepared a series of 3- and 4-(phosphonoalkyl)pyridine- and -piperidine-2-carboxylic acids as antagonists of neurotransmission at N-methyl-D-aspartate (NMDA) preferring receptors. NMDA antagonists may prove to be useful therapeutic agents, for instance, as anticonvulsants, in the treatment of neurodegenerative disorders such as Alzheimer's disease and in the prevention of neuronal damage that occurs during cerebral ischemia. The compounds prepared were evaluated for their ability to displace [3H]CPP binding (an assay shown to be selective for compounds that bind at the NMDA receptor) and for their ability to block NMDA-induced lethality in mice (an assay that is also specific for competitive and noncompetitive NMDA antagonists). Two of the compounds, cis-4-(phosphonomethyl)piperidine-2-carboxylic acid (11a) and cis-4-(3-phosphonoprop-1-yl)piperidine-2-carboxylic acid (11c) proved to be potent NMDA antagonists. 11a and 11c displaced [3H]CPP binding with IC50's of 95 and 120 nM, respectively, and both protected mice from NMDA-induced lethality, with MEDs (minimum effective dose, the dose at which three of the five animals tested survived) of 10 and 40 mg/kg ip, respectively. The rest of the compounds prepared were weakly active or inactive in these assays. The pattern of activity observed for this series parallels that observed for the acyclic series of omega-phosphono-alpha-amino acids, where AP5 and AP7 possessed NMDA antagonist activity while AP6 and AP8 were inactive. Reduction of conformational mobility by incorporation of the piperidine ring led to enhanced potency relative to the acyclic analogues.

Glutamatergic mechanisms for speed control and network operation in the rodent locomotor CPG

“…The following glutamate receptor agonists were used in combination with 5HT and DA: N -methyl- d -aspartate (NMDA; 1–16 μM) (Cazalets et al 1992), d -glutamate ( d -Glu) (100–1000 μM), the non-NMDAR agonist kainate (KA, 0.3–2 μM) (Cazalets et al 1992), and the GluR5 kainate receptor agonist (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4yl)propanoic acid (ATPA, 0.3–5 μM; Tocris) (Procter et al, 1998; Kaminski et al, 2004; Xu et al, 2006). The following glutamate receptor antagonists were used: the broad spectrum non-NMDAR blocker, 2,3-Dioxo 6-nitro-1,2,3,4 tetrahydrobenzo[f]quinoxaline 7-sulfonamide (NBQX, 10 μM) (Menuz et al, 2007); the competitive NMDA receptor blocker, d -(-)-2-amino-5-phosphonopentanoic acid (AP5, 30–60 μM) (Childs et al, 1988; Ornstein et al, 1989); the non-competitive NMDAR blocker (5S,10R)-( + )-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801, 50 μM Tocris) (Childs et al, 1988; Huettner and Bean, 1988); the GluR5-subunit containing kainate receptor (KAR) blocker (S)-1-(2-amino-2-carboxyethyl)-3-(2-carboxybenzyl)pyrimidine-2,4-dione (UBP 302; Tocris) dissolved in 10 mM NaOH (10 mM stock) for a working concentration of 1–12 μM (Mayer et al, 2006; Ireland et al, 2008; Wondolowski and Frerking, 2009); the AMPA receptor blocker 4-(8-Methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzenamine hydrochloride, (GYKI 52466 hydrochloride; Tocris) dissolved either in DMSO (stock 20 mM) or in 0.05–0.1 M HCl (stock 10 mM) for working concentrations of 20 μM (Loscher and Honack, 1994; Micale et al, 2002). The concentrations of DMSO, HCl and other solvents used did not produce any effects by themselves on the locomotor-like activity.…”

Receptor interaction profile and CNS general pharmacology of metrifonate and its transformation product dichlorvos in rodents

“…These are rather heterogeneous. Some derivatives are known to bind to muscarinic and nicotinic autoreceptors [Rao et al, 1987;Ward et al, 1993;Bakry et al, 19881, while others, such as phosphonoalkylpyridines or phosphonoalkanoic acids, are potent competitive NM DA receptor antagonists [Bigge et al, 1989;Ornstein et al, 1989;Vazquez et al, 19921, which induce behavioral effects related to NMDA antagonism [Millan, 19911. Others, i.e., diazinon or soman, are reported to interact with other neurotransmitter systems, such as the serotoninergic system [Rajendra et al, 1986; el Etri et al, 19921.…”

Ozonolysis of some 8-alkoxyquinolines, and synthesis of a precursor to the non-sedating antihistamine Claritin

“…30,31 8-Isopropoxyquinoline 29 was also successfully ozonised in methanol at 0 o C to give the expected aldehydo-ester 30 in excellent yield after reductive work-up using dimethyl sulfide. An alternative multi-step synthesis of this compound from quinolinic anhydride has been described, 32 but the overall yield obtained using that route was only ca. 20%.…”

“…The crude oily product (13.4 g; 99%) was used without further purification for olefination reactions, but an analytical sample of the aldehyde 30 was obtained by column chromatography (EtOAc/hexane) as an oil (lit. 32 C and treated with n-butyllithium (2.5M in hexane: 2 mL; 5 mmol). After 30 min the temperature was decreased to -78 °C and the aldehyde 25 (0.8 g; 4.8 mmol), dissolved in THF (10 mL), was added.…”