Comparative molecular field analysis and synthetic validation of a hydroxyamide-propofol binding and functional block of neuronal voltage-dependent sodium channels

Abstract

Voltage gated sodium channels represent an important therapeutic target for a number of neurological disorders including epilepsy. Unfortunately, medicinal chemistry strategies for discovering new classes of antagonist for trans-membrane ion channels have been limited to mostly broad screening compound arrays. We have developed new sodium channel antagonist based on a propofol scaffold using the ligand based strategy of comparative molecular field analysis (CoMFA). The resulting CoMFA model was correlated and validated to provide insights into the design of new antagonists and to prioritize synthesis of these new structural analogues (compounds 4 and 5) that satisfied the steric and electrostatic model. Compounds 4 and 5 were evaluated for [3H]-batrachotoxinin-A-20-α-benzoate ([3H]-BTX-B) displacement yielding IC50's of 22 and 5.7 μM, respectively. We further examined the potency of these two compounds to inhibit neuronal sodium currents recorded from cultured hippocampal neurons. At a concentration of 50 μM, compounds 4 and 5 tonically inhibited sodium channels currents by 59 ± 7.8% (n=5) and 70 ± 7.5% (n=7) respectively. This clearly demonstrates that these compounds functionally antagonize native neuronal sodium channel currents. In summary, we have shown that CoMFA can be effectively used to discover new classes of sodium channel antagonists.

Development of pharmacophoric maps for cardiovascular depression by intravenous anaesthetic agents: comparison with maps for immobilizing activity

“…Furthermore, the pharmacophore map for immobilization shows similarities to that for propofol alone in its alignment in the paper from Brown and colleagues. 40 The cardiovascular model using the same lead conformer of eltanolone as previously gave very similar results to an earlier preliminary model which was based on molecular similarity indices but to a different lead compound-ORG 21465, where the r 2 was 0.918, q 2 0.623, F 1,6 67.276, 41 so adding further support to the robustness of the present derived cardiovascular pharmacophore.…”

Palladium‐Catalyzed Decarbonylative Dehydration for the Synthesis of α‐Vinyl Carbonyl Compounds and Total Synthesis of (−)‐Aspewentins A, B, and C

“…[19] We commenced our total synthesis by copper-catalyzed coupling of aGrignard reagent derived from 14 with ethyl 4iodobutyrate (Scheme 4). [20] a-Methylation of the coupled product produces the ester 15,which was saponified and then cyclized to form the tricyclic ketone 13.T he ketone was converted into the corresponding allyl enol carbonate (16), which was then subjected to palladium-catalyzed enantioselective decarboxylative allylic alkylation to afford the allyl ketone 12 in nearly quantitative yield and 94 % ee.I nterestingly,t he allylic alkylation reaction proceeds efficiently with al ow palladium catalyst loading, employing an ew catalytic protocol recently developed by our group. [21] Only 2.7 mg of Pd(OAc) 2 is needed for ar eaction of 1.42 grams of starting material (16)t od eliver 1.25 grams of allyl ketone product (12).…”

“…[20] α-Methylation of the coupled product produces ester 15 , which was saponified and then cyclized to form tricyclic ketone 13 . The ketone was converted to the corresponding allyl enol carbonate ( 16 ), and subjected to palladium-catalyzed enantioselective decarboxylative allylic alkylation to afford allyl ketone 12 in nearly quantitative yield and 94% ee.…”

Tritium-labelled alkaloids: Synthesis and applications

“…The expected technical challenges confronting the tritiation of batrachotoxin were cleverly avoided by the development of a convenient surrogate radioligand [20‐benzoate‐ 3 H]batrachotoxinin A 20‐benzoate . Nearly 200 publications have appeared using this radioligand to explore voltage‐gated sodium channels . The steroid‐derived alkaloid tomatidine ( 29 ) was tritium labelled in a sequence of steps involving first oxidation of a 3‐position alcohol to the ketone tomatidone.…”

“…147 Nearly 200 publications have appeared using this radioligand to explore voltage-gated sodium channels. 148,149 The steroid-derived alkaloid tomatidine (29) was tritium labelled in a sequence of steps involving first oxidation of a 3-position alcohol to the ketone tomatidone. Next, a general exchange of tomatidone using tritiated water introduced tritium into the flanking 2-and 4-positions.…”