Biomedical subjects
Publications and source records attributed to J C Jerman.
Optimisation of novel cis- and trans-4-(substituted-amido)benzopyran-3-ol derivatives has led to the identification of SB-220453 20 with an in vivo pre-clinical CNS profile predictive of potential antimigraine activity.
A series of N-(tetrahydroisoquinolinyl)-2-methoxybenzamides was identified by high-throughput screening at the novel SB-204269 binding site. SAR studies have provided compounds 4 and 14 with high affinity and good anticonvulsant activity in animal models.
1. SB-204269 (trans-(+)-6-acetyl-4S-(4-fluorobenzoylamino)-3, 4-dihydro-2,2-dimethyl-2H-benzol[b]pyran-3R-ol, hemihydrate) shows potent anticonvulsant activity in a range of animal seizure models, with a lack of neurological or cardiovascular side-effects. The profile of the compound suggests that it may have a novel mechanism of action. This study describes the characteristics of a binding site for [3H]-SB-204269 in rat forebrain membranes. 2. Specific [3H]-SB-204269 binding was saturable and analysis indicated binding to a homogenoeous population of non-interacting binding sites with a dissociation constant (KD) of 32 +/- 1 nM and a maximum binding capacity (Bmax) of 253 +/- 18 fmol mg-1 protein. Kinetic studies indicated monophasic association and dissociation. Binding was similar in HEPES or Tris-HCl buffers and was unaffected by Na+, K+, Ca2+ or Mg2+ ions. Specific binding was widely distributed in brain, but was minimal in a range of peripheral tissues. 3. Specific [3H]-SB-204269 binding was highly stereoselective, with a 1000 fold difference between the affinities of SB-204269 and its enantiomer SB-204268 for the binding site. The affinities of analogues of SB-204269 for binding can be related to their activities in the mouse maximal electroshock seizure threshold (MEST) test of anticonvulsant action. 4. None of the standard anticonvulsant drugs, phenobarbitone, phenytoin, sodium valproate, carbamazepine, diazepam and ethosuximide, or the newer anticonvulsants, lamotrigine, vigabatrin, gabapentin and levetiracetam, showed any affinity for the [3H]-SB-204269 binding site. A wide range of drugs active at amino acid receptors, Na+ or K+ channels or various other receptors did not demonstrate any affinity for the binding site. 5. These studies indicate that SB-204269 possesses a specific CNS binding site which may mediate its anticonvulsant activity. This binding site does not appear to be directly related to the sites of action of other known anticonvulsant agents, but may have an important role in regulating neuronal excitability.
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Pharmacologists are often required to analyse nonlinear experimental effects by fitting the data to defined theoretical models. This may require a specialized computer program capable of performing nonlinear regression analysis, which can prove costly given the variety of pharmacological research. Here, Wayne Bowen and Jeff Jerman describe a generic method of performing nonlinear regression using spreadsheet applications, and demonstrate how this approach can be used to create automated systems of data analysis.
A simple high performance liquid chromatographic method has been devised for the measurement of bisoprolol in plasma or serum. The sample (200 microL) is vortex mixed for 30 s with 2 M Tris solution (50 microL), aqueous internal standard (benzimidazole, 2.0 mg/L, 50 microL) and methyl t-butyl ether (200 microL). After centrifugation (9950 x g, 2 min), a portion of the resulting extract is analysed on a microparticulate (5 microns) silica column using 1 mM camphorsulphonic acid in methanol as the mobile phase. Detection is by fluorescence at an excitation wavelength of 215 nM. The lower limit of accurate measurement for the assay is 10 micrograms/L (CV% = 8.9, n = 9) with a lower limit of detection of 5 micrograms/L. There is minimal interference from either commonly prescribed drugs or endogenous compounds.