PMID- 24773376 OWN - NLM STAT- MEDLINE DCOM- 20150619 LR - 20191027 IS - 1875-6638 (Electronic) IS - 1573-4064 (Linking) VI - 10 IP - 8 DP - 2014 TI - Syntheses and N-methyl-D-aspartate receptor antagonist pharmacology of fluorinated arylcycloheptylamines. PG - 843-52 AB - 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 [(3)H]-(+)-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 (Ki) 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. FAU - Sun, Shengguo AU - Sun S FAU - Wallach, Jason AU - Wallach J FAU - Adejare, Adeboye AU - Adejare A AD - Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA 19104, USA. a.adejar@usciences.edu. LA - eng GR - 7R15N536393-04/PHS HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PL - Netherlands TA - Med Chem JT - Medicinal chemistry (Shariqah (United Arab Emirates)) JID - 101240303 RN - 0 (Amines) RN - 0 (Anticonvulsants) RN - 0 (Cycloheptanes) RN - 0 (Neuroprotective Agents) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 10028-17-8 (Tritium) RN - 6LR8C1B66Q (Dizocilpine Maleate) RN - J1DOI7UV76 (Phencyclidine) SB - IM MH - Amines/*chemical synthesis/chemistry/pharmacology MH - Animals MH - Anticonvulsants/*chemical synthesis/chemistry/pharmacology MH - Ataxia/*drug therapy/metabolism/physiopathology MH - Binding Sites MH - Binding, Competitive MH - Cycloheptanes/*chemical synthesis/chemistry/pharmacology MH - Dizocilpine Maleate/metabolism/pharmacology MH - Electroshock MH - Halogenation MH - Hippocampus/cytology/drug effects/metabolism MH - Neurons/cytology/drug effects/metabolism MH - Neuroprotective Agents/*chemical synthesis/chemistry/pharmacology MH - Phencyclidine/metabolism/pharmacology MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, N-Methyl-D-Aspartate/*antagonists & inhibitors/chemistry/metabolism MH - Structure-Activity Relationship MH - Tissue Culture Techniques MH - Tritium EDAT- 2014/04/30 06:00 MHDA- 2015/06/20 06:00 CRDT- 2014/04/30 06:00 PHST- 2013/10/11 00:00 [received] PHST- 2014/03/30 00:00 [revised] PHST- 2014/04/13 00:00 [accepted] PHST- 2014/04/30 06:00 [entrez] PHST- 2014/04/30 06:00 [pubmed] PHST- 2015/06/20 06:00 [medline] AID - MC-EPUB-60290 [pii] AID - 10.2174/1573406410666140428104444 [doi] PST - ppublish SO - Med Chem. 2014;10(8):843-52. doi: 10.2174/1573406410666140428104444.