Gyógyszerészet, farmakogenomika, gyógyszerkutatás és tervezés, gyógyszeres kezelés
In this work, we report on the in vitro and in vivo pharmacological properties of
LP1 analogs to complete the series of structural modifications aimed to generate compounds
with improved analgesia. To do that, the phenyl ring in the N-substituent of our lead
compound LP1 was replaced by an electron-rich or electron-deficient ring and linked
through a propanamide or butyramide spacer at the basic nitrogen of the (−)-cis-N-normetazocine
skeleton. In radioligand binding assays, compounds 3 and 7 were found to display nanomolar
binding affinity for the μ opioid receptor (MOR) (Ki = 5.96 ± 0.08 nM and 1.49 ± 0.24
nM, respectively). In the mouse vas deferens (MVD) assay, compound 3 showed an antagonist
effect against DAMGO ([D-Ala2, N-MePhe4, Gly-ol]-enkephalin), a highly selective MOR
prototype agonist, whereas compound 7 produced naloxone reversible effect at MOR.
Moreover, compound 7, as potent as LP1 and DAMGO at MOR, was able to reduce thermal
and inflammatory pain assessed by the mouse tail-flick test and rat paw pressure thresholds
(PPTs) measured by a Randall–Selitto test.
