Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release.

Human genetic studies show that the voltage gated sodium channel 1.7 (Nav1.7) is a key molecular determinant of pain sensation. However, defining the Nav1.7 contribution to nociceptive signalling has been hampered by a lack of selective inhibitors. Here we report two potent and selective arylsulfonamide Nav1.7 inhibitors; PF-05198007 and PF-05089771, which we have used to directly interrogate Nav1.7's role in nociceptor physiology. We report that Nav1.7 is the predominant functional TTX-sensitive Nav in mouse and human nociceptors and contributes to the initiation and the upstroke phase of the nociceptor action potential. Moreover, we confirm a role for Nav1.7 in influencing synaptic transmission in the dorsal horn of the spinal cord as well as peripheral neuropeptide release in the skin. These findings demonstrate multiple contributions of Nav1.7 to nociceptor signalling and shed new light on the relative functional contribution of this channel to peripheral and central noxious signal transmission.The funder provided support in the form of salaries for authors [AA, AB, MC, JT, MM, AW, EP, AG, PJC, RD, DP, ZL, BM, CW, NS, RS, PS, NC, DK, RB, ES], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section

Organocatalytic asymmetric total synthesis of (R)-rolipram and formal synthesis of (3S,4R)-paroxetine.

An efficient enantioselective total synthesis of (R)-rolipram and an efficient enantioselective formal synthesis of (3S,4R)-paroxetine has been achieved using the highly enantioselective Michael addition of malonate nucleophiles as key steps in both cases

Catalytic enantioselective rearrangements and cycloadditions involving ylides from diazo compounds

This review summarizes the background and state of the art (as of June 2000) of catalytic enantioselective rearrangements and cycloadditions involving ylides from diazo compounds. The field is still in its infancy, as until a few years ago it was not considered likely that a catalyst, having decomposed a diazo compound to form an ylide, would still be able to exert an influence on subsequent transformations of the ylide. Recent developments have shown this not to be the case and a new era of synthetically important ylide transformations in organic chemistry has begun where appropriate metal-chiral (nonracemic) ligand combinations are starting to be developed to render these transformations enantioselective

Catalytic enantioselective tandem carbonyl ylide formation-cycloaddition

Catalytic enantioselective tandem carbonyl ylide formation-cycloaddition of α-diazo-β-ketoesters 1 (R = alkyl, n = 1,2) using 1 mol% [Rh2(S-DOSP)4] 2 in hexane at room temperature to give the cycloadducts 3 in good yields and up to 53% ee are described

Enantioselective intramolecular 1,3-dipolar cycloadditions of diazocarbonyl-derived oxidopyryliums

Catalytic enantioselective tandem oxidopyrylium formation - intramolecular 1,3-dipolar cycloaddition reactions of phthalic anhydride-derived unsaturated diazocarbonyl compounds in up to 19% ee are described

Bicyclo[10.2.1]pentadecenone derivatives by free radical macrocyclisation

The synthesis of intermediates for the preparation of stereoisomeric bicyclo[10.2.1]pentadec-13-en-3-ones is described. The preparation and the addition of 6-functionalised hexylcuprate reagents to bicyclic lactone 5 is discussed and a method described for the epimerisation of the so-formed trans-disubstituted cyclopentene derivatives. The cis- and trans-1,4-disubstituted cyclopentenes are both shown to undergo 13-endo-trig cyclisation affording the title bicyclic compounds in moderate yield

Efficient Rh-II binaphthol phosphate catalysts for enantioselective intramolecular tandem carbonyl ylide formation-cycloaddition of alpha-diazo-beta-keto esters

Catalytic enantioselective tandem carbonyl ylide formation-cycloadditions of α-diazo-β-keto ester 1 using 0.5 mol% dirhodium tetrakis(1,1'-binaphthyl-2,2'-diyl phosphate) catalysts 7-9 and 14 to give the cycloadduct 3 in good yields and up to 90% ee are described