Određivanje strukture farmakofore antagonista angiotenzinskih AT1 receptora i hemometrijski pristup optimizaciji HPLC metode za određivanje losartana, valsartana i irbesartana
Identification of pharmacophore of at1 receptor antagonists and chemometric approach in hplc method optimization for determination of losartan, valsartan and irbesartan.
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AT1 receptori posreduju u skoro svim poznatim fiziološkim djelovanjima
angiotenzina II (Ang II): u kardiovaskularnim, bubrežnim, nervnim, endokrinim ćelijama,
jetrenim i drugim ciljnim ćelijama. Ta djelovanja uključuju regulaciju arterijskog krvnog
pritiska, održavanje balansa vode i elektrolita, žeđ, lučenje hormona i bubrežnu funkciju.
AT2 receptori se nalaze u srži nadbubrežne žlijezde, maternici i u tkivu fetusa. Pretpostavlja
se da ovi receptori igraju ulogu u razvoju fetusa i nisu bitnije uključeni u kontrolu krvnog
pritiska. Vezujući se za AT1 receptor Ang II izaziva konformacijske promjene u molekuli
receptora što dovodi do interakcije receptora sa G proteinom i prenosa signala preko
nekoliko transmembranskih sistema (enzimski sistemi, naponski ovisni kalcijevi kanali,
itd.).
Antagonisti angiotenzina II imaju 10.000 puta veći afinitet vezivanja za AT1 receptore nego
za AT2 receptore (visokoselektivni blokatori AT1 receptora). Blokatorima AT1 receptora
pripadaju: losartan, valsa...rtan, irbesartan, kandesartan, eprosartan, telmisartan i olmesartan
(“sartani”). Svi antagonisti AT1 receptora su jedinjenja slične hemijske strukture koju
karakteriše prisustvo bifenila sa kiselom funkcionalnom grupom (karboksilna ili tetrazol).
Glavna primjena je u liječenju hipertenzije, dijabetičke nefropatije i kongestivnog zatajenja
srca, gdje se koriste samostalno ili u kombinaciji sa diureticima i drugim
antihipertenzivima.
U cilju dizajniranja novih AT1 blokatora primijenjena je kompjuterska metoda. 3D-QSAR
studija je izvedena korištenjem baze podataka od 49 AT1 blokatora od kojih je 32 služilo
kao trening set, a 17 kao test set. Za razvoj 3D-QSAR modela i odabir najznačajnijih
molekulskih deskriptora primijenjena je metoda PLS regresije (Partial Least Squares
regression)...
AT1 receptors mediate almost all known physiological effects of angiotensin II
(Ang II): cardiovascular, renal, nervous, endocrine cells, liver and other target cells. These
actions include blood pressure regulation, balance of water and electrolytes maintaining,
thirst, hormone secretion and renal function. AT2 receptors are found in the adrenal gland,
uterus and fetal tissue. It is assumed that these receptors play a role in fetal development.
AT2 are not substantially involved in blood pressure control. Binding with AT1 receptor
Ang II causes a conformational change of the receptor molecules resulting in receptor - G
proteins interaction and signal transmission through several transmembrane systems
(enzyme systems, voltage dependent calcium channels, etc.). Angiotensin II antagonists
show 10.000 times greater binding affinity for the AT1 receptor than AT2 receptors; they
are highly selective for AT1 receptor. Angiotensin II antagonists include: losartan,
valsartan, irbesartan, cande...sartan, eprosartan, telmisartan and olmesartan ("sartans").
Chemical structures of AT1 receptor antagonists are similar and consist of biphenyl group
and an acidic functional group (carboxylic or tetrazole). Angiotensin II receptor blockers
are primarily used for the treatment of hypertension, diabetic nephropathy, congestive heart
failure. They are used alone or in combination with other antihypertensive drugs and
diuretics.
In order to design new AT1 blockers computerized methods were applied. The 3D-QSAR
study was performed on a data set composed of 49 ARBs with 32 AT1 blockers in the
training set and 17 AT1 blockers in the test set. The PLS regression has been applied on
selection of the most relevant molecular descriptors and 3D-QSAR models building.
Obtained results demonstrated good predicting capacity of the created 3D-QSAR model for
the training set molecules and model was further used to predict the pKi values of the test
set...