Michael Geoffrey Neil Russell

Modulation of [ 3H]MK-801 binding to NMDA receptors in vivo and in vitro

[3H]MK-801 binding in vivo was used to determine the occupancy of NMDA receptor ligands shown to allosterically modulate binding in vitro. ED(50) values (mg/kg) were obtained for the channel blockers (+)-5-methyl-10,11-dihydro-5,4-dibenzo[a,d]cyclohepten-5,10-imine maleate ((+)-MK-801, 0.2), 1-(1-phenylcyclohexyl)piperidine (phencyclidine, PCP, 1.7) and ketamine (4.4). Antagonists at the glutamate (DL-(2-carboxypiperazine-4-yl)propyl-1-phosphonate (DL-CPP, 5.7)) and glycine site (7-Chloro-4-hydroxy-3-(3-phenoxy)-phenyl-2(H)quinolinone (L-701,324, 14.1), 3R(+)cis-4-methyl-pyrrollid-2-one (L-687,414, 15.1)) inhibited [3H]MK-801 binding in vivo to varying maximum levels (69%, 103% and 45%, respectively). NR2B subunit-selective compounds acting at the ifenprodil site inhibited [3H]MK-801 in vivo by a maximum of 52-72% and gave ED(50) values (mg/kg) of: (+/-)-(1S*, 2S*)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol ((+/-)CP-101,606), 1.9; (+/-)-(3R, 4S)-3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol ((+/-)CP-283,097), 1.8; (+/-)-(R*, S*)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidine propanol ((+/-)Ro 25-6981), 1.0; ifenprodil, 6.0. The glycine site agonist D-serine stimulated binding to 151% of control with an ED(50) of 1.7 mg/kg. Results show that [3H]MK-801 binding in vivo may be used to measure receptor occupancy of ligands acting not only within the ion channel but also at modulatory sites on the NMDA receptor complex.

2,7-Diazabicyclo[3.3.0]octanes as novel h5-HT1D receptor agonists

The conformational restriction of a (benzylamino)methyl substituted pyrrolidine to form 2,7-diazabicyclo[3.3.0]octanes has led to a series of compounds with high affinity at the h5-HT1D receptor as well as dramatically increased concentrations in the hepatic portal vein following oral administration.

Asymmetric synthesis of the northern segment of ephedradine C. A novel dihydrobenzo[b]furan formation

An asymmetric synthesis of the dihydrobenzo[b]furan segment of ephedradine C has been achieved utilising a chiral oxazolidinone in an aldol reaction to form a β-hydroxy ester, followed by a novel debenzylation and concomitant intramolecular cyclisation with iodotrimethylsilane as key steps. An asymmetric Michael reaction with a homochiral lithium amide was used to form the third and final chiral centre.

Synthesis and serotonergic activity of benzofuran and dihydrogenzofuran analogues of 5-carboxamidotryptamine.

The syntheses of the benzofuran ( 1 ) and dihydrobenzofuran ( 10 ) analogues of 5-carboxamidotryptamine ( 5-CT ) were accomplished utilising a Horner-Emmons reaction on a benzofuranone. Compound 1 was a relatively potent 5-HT 1D agonist, although less potent than 5-CT . Mo studies were carried out to investigate this difference.

Asymmetric synthesis of the northern segment of ephedradine C

An asymmetric synthesis of the dihydrobenzofuran segment of ephedradine C has been achieved. Key steps include a chiral oxazolidinone-mediated aldol reaction to form a β-hydroxy ester, followed by a novel debenzylation and concomitant intramolecular cyclisation with iodotrimethylsilane. An asymmetric Michael reaction with a homochiral lithium amide was used to form the third and final chiral centre. The absolute stereochemistry of these three centres was confirmed by X-ray crystal-structure determinations.