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Napetostno odvisni natrijevi kanalčki (Nav) so transmembranski proteini, ki imajo pomembno vlogo pri električnem signaliziranju celic in so izjemnega pomena za normalno delovanje človeka. V terapijo je uvedenih nekaj neselektivnih zaviralcev Nav, ki jih uporabljamo kot lokalne anestetike (npr. lidokain), antiaritmike razreda I (npr. meksiletin), antiepileptike (npr. karbamazepin) in antidepresive (npr. amitriptilin). Te učinkovine pa so zaradi njihove neselektivnosti za različne podtipe Nav znane po ozkem terapevtskem indeksu in številnih neželenih učinkih na centralno živčni sistem in srce. V zadnjih letih so izvedli številne raziskave na področju razvoja selektivnih zaviralcev različnih podtipov Nav, predvsem podtipa Nav1.7, ki je udeležen v bolečinskih poteh. Kljub temu do danes še niso odkrili dobrega selektivnega zaviralca Nav1.7, ki bi ga lahko uporabljali kot sredstvo za zdravljenje bolečine. Raziskave kažejo, da je za prevajanje bolečine odgovoren tudi kanalček Nav1.3, ki je poleg bolečinskih poti udeležen tudi pri vnetju in nevrorazvojnih motnjah. V sklopu magistrske naloge smo načrtovali pripravo spojin, ki bi se vezale na vezavno mesto na četrti domeni za zaznavo napetosti (VSD4) kanalčka Nav1.3 in bi izkazovale dobro zaviralno delovanje in selektivnost na Nav1.3. Ta kanalček je manj raziskan, vendar predstavlja zelo pomembno tarčo za odkrivanje novih učinkovin za zdravljenje bolečine, vnetja in nevrorazvojnih motenj. Za izhodišče so nam služili arilsulfonamidni zaviralci Nav1.3, ki so jih predhodno pripravili raziskovalci Katedre za farmacevtsko kemijo na Fakulteti za farmacijo Univerze v Ljubljani. Pripravili smo dve končni spojini ter ovrednotili njuno istovetnost in čistost z jedrsko magnetno resonanco, infrardečo spektroskopijo in masno spektrometrijo visoke ločljivosti. Obe končni spojini imata enak arilsulfonamidni del, ki je ključen za zaviranje Nav, kot spojina, ki smo jo želeli optimizirati. Del, ki je odgovoren za selektivnost, pa smo želeli optimizirati tako, da smo v strukturo molekule vključili bazičen dušikov atom, ki bi tvoril dodatne interakcije v vezavnem mestu VSD4 in s tem močneje in bolj selektivno zaviral Nav1.3. Voltage-gated sodium channels (Nav) are transmembrane proteins that play an important role in electrical signalling in cells and are essential for normal human function. There are several non-selective Nav inhibitors already in use as therapeutic agents, such as local anaesthetics (e.g. lidocaine), class I antiarrhythmics (e.g. mexiletine), antiepileptics (e.g. carbamazepine), and antidepressants (e.g. amitriptyline). However, due to their non-selectivity for different subtypes of voltage-gated sodium channels, these drugs are known to have a narrow therapeutic index and many adverse effects on the central nervous system and heart. In recent years, much research has been done in this field, in particular on the Nav1.7 subtype involved in pain pathways. However, to date, we have not found a good and selective Nav1.7 inhibitor that can be used for the treatment of pain. Studies suggest that Nav1.3, which is involved in inflammation and neurodevelopmental diseases in addition to pain pathways, is also responsible for pain transmission. As part of my master's thesis, we designed compounds that bind to the binding site on the voltage sensing domain 4 (VSD4) of Nav1.3 and exhibit good inhibitory activity and selectivity on Nav1.3. To date, this channel has been less explored, but it represents a very important target for the discovery of new drugs for the treatment of pain, inflammation, and neurodevelopmental diseases. Our goal was to optimise arylsulfonamide inhibitors of Nav1.3 prepared by researchers from the Department of Pharmaceutical Chemistry at the Faculty of Pharmacy, University of Ljubljana. We succeeded in synthesising two final compounds and evaluated their identity and purity with nuclear magnetic resonance, infrared spectroscopy and high-resolution mass spectrometry. The two final compounds possess the same arylsulfonamide moiety responsible for the inhibition of Nav channels as the compound we aimed to optimise. The part responsible for selectivity was optimised by incorporating a basic nitrogen atom into the structure of the molecule, which can form additional interactions in the VSD4 binding site and thus inhibit Nav1.3 more strongly and selectively. |
