Syntheses and N-methyl-D-aspartate Receptor Antagonist Pharmacology of Fluorinated Arylcycloheptylamines

Title:Syntheses and N-methyl-D-aspartate Receptor Antagonist Pharmacology of Fluorinated Arylcycloheptylamines

Volume: 10 Issue: 8

Author(s): Shengguo Sun, Jason Wallach and Adeboye Adejare

Affiliation:

Keywords: Arylcycloheptylamines, arylcyclohexylamines, fluorinated PCP analogs, N-methyl-D-aspartate receptor, phencyclidine, NMDAR antagonists.

Abstract: Selective uncompetitive antagonists of the phencyclidine (PCP) binding site of the N-methyl-D-aspartate receptor (NMDAR) are known to have therapeutic potential as anticonvulsants and neuroprotective agents. Several fluorinated molecules with each containing a cycloheptane ring were designed to probe the PCP pharmacophore and test the influence of fluorine substitution on NMDAR binding and in vivo efficacy. Syntheses and analyses of six novel compounds, 1-(4- fluorophenyl)cycloheptanamine (3), 1-(1-(4-fluorophenyl)cycloheptyl)piperidine (4), 1-(1-(4-fluorophenyl)cycloheptyl) pyrrolidine (5), 1-(3-fluorophenyl)cycloheptanamine (6), 1-(1-(3-fluorophenyl)cycloheptyl)piperidine (7), 1-(1-(3-fluorophenyl) cycloheptyl)pyrrolidine (8) and several related reference arylcyloalkylamines are described. Receptor binding was performed at the PCP site of NMDAR for each compound using [³H]-(+)-MK-801 displacement. Unexpectedly, the 3- fluoro- primary amine 6 had the greatest affinity of the series and these binding results support a different structure activity relationship (SAR) profile for arylcycloheptylamines when compared to arylcyclohexylamines like PCP. Five of the novel compounds have affinity (K_i) in the hundred nM (10^-7) range. In addition, compounds 3, 5, 6, 7 and 8 were evaluated and found to exhibit neuroprotective effects from NMDA induced toxicity in vitro and compounds 6, 7 and 8 exhibited anticonvulsant activities in rats. An ED₅₀ of 13.84 mg/kg was found for compound 6 in rat maximal electroshock (MES) test with a protective index (PI) of 3.66 against ataxia. These results support further investigation of the arylcycloheptylamine class.

Cite this article as:

Sun Shengguo, Wallach Jason and Adejare Adeboye, Syntheses and N-methyl-D-aspartate Receptor Antagonist Pharmacology of Fluorinated Arylcycloheptylamines, Medicinal Chemistry 2014; 10 (8) . https://dx.doi.org/10.2174/1573406410666140428104444