Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Comparative Molecular Field Analysis (CoMFA) is one of the most powerful modern tools for quantitative structure-activity relationship studies. The CoMFA predictability is conventionally characterized by a cross-validated correlation coefficient R2 (q2). Our CoMFA investigation of 4 datasets, including 7 cephalotaxine esters, 20 5-HT1A receptor ligands, 59 inhibitors of HIV protease, and 21 steroids reveals that the q2 value is sensitive to the overall orientation of superimposed molecules on a computer terminal and can vary by as much as 0.5q2 units when the orientation is varied by systematic rotation. To optimize CoMFA, we have developed a new routine, cross-validated R2-guided region selection (q2-GRS). We first subdivide the rectangular lattice obtained initially with conventional CoMFA into 125 small boxes and perform 125 independent analyses using probe atoms placed within each box with the step size of 1.0 A. We then select only those small boxes for which a q2 is higher than a specified optimal cutoff value. Finally, we repeat CoMFA with the union of small boxes selected at the previous step. Four datasets described above were used to validate this new q2-GRS routine. In each case we have obtained an orientation-independent, high q2, exceeding the one obtained with the conventional CoMFA. This method shall be used routinely in the future CoMFA studies to guarantee the reproducibility of the reported q2 values.
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PMID:Cross-validated R2-guided region selection for comparative molecular field analysis: a simple method to achieve consistent results. 770 9

1. Previous studies have shown that flupirtine, a centrally acting, non-opioid analgesic agent, also exhibits neuroprotective activity in focal cerebral ischaemia in mice and reduces apoptosis induced by NMDA, gp 120 of HIV, prior protein fragment or lead acetate as well as necrosis induced by glutamate or NMDA in cell culture. To study the potential mechanism of the neuroprotective action of flupirtine, we investigated whether flupirtine is able to modulate potassium or NMDA-induced currents in rat cultured hippocampal neurones by use of the whole-cell configuration of the patch-clamp technique. 2. We demonstrated that 1 microM flupirtine activated an inwardly rectifying potassium current (K(ir)) in hippocampal neurones (deltaI=-39+/-18 pA at -130 mV; n=10). This effect was dose-dependent (EC50=0.6 microM). The reversal potential for K(ir) was in agreement with the potassium equilibrium potential predicted from the Nernst equation showing that K(ir) was predominantly carried by K+. Furthermore, the induced current was blocked completely by Ba2+ (1 mM), an effect typical for K(ir). 3. The activation of K(ir) by flupirtine was largely prevented by pretreatment of the cells with pertussis toxin (PTX) indicating the involvement of a PTX-sensitive G-protein in the transduction mechanism (deltaI=-3+/-6 pA at -130 mV; n=8). Inclusion of cyclic AMP in the intracellular solution completely abolished the activation of K(ir) (n=7). 4. The selective alpha2-adrenoceptor antagonist SKF-86466 (10 microM), the selective 5-HT1A antagonist NAN 190 as well as the selective GABA(B) antagonist 2-hydroxysaclofen (10 microM) failed to block the flupirtine effect on the inward rectifier. 5. Flupirtine (1 microM) could not change the current induced by 50 microM NMDA. 6. These results show that in cultured hippocampal neurones flupirtine activates an inwardly rectifying potassium current and that a PTX-sensitive G-protein is involved in the transduction mechanism.
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PMID:Influence of flupirtine on a G-protein coupled inwardly rectifying potassium current in hippocampal neurones. 942 Dec 79