RESUMO
The antihypertensive activity of two αs1-casein-derived peptides and casein hydrolysate containing these sequences was evaluated in the presence of naloxone. The activity was abolished by this opioid antagonist at 2, 4, and 6 h post-administration. Similarly, the antihypertensive effect of the αs1-casein peptides 90RYLGY94 (-23.8 ± 2.5 mmHg) and 143AYFYPEL149 (-21.1 ± 3.2 mmHg) at 5 mg/kg of body weight was antagonized by the co-administration of naloxone. Because peptide 143AYFYPEL149 had recently shown opioid activity, a molecular dynamic simulation of this peptide with human µ-opioid receptor was performed to demonstrate its favorable structure and interaction energy, despite the presence of Ala at the N terminus. Altogether, these results revealed that the in vivo effect on systolic blood pressure of the studied αs1-casein peptides is mediated by interaction with opioid receptors and the antihypertensive activity of casein hydrolysate can be very likely ascribed to them with the possible contribution of other mechanisms.
Assuntos
Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Caseínas/administração & dosagem , Hipertensão/tratamento farmacológico , Peptídeos/administração & dosagem , Receptores Opioides/metabolismo , Animais , Anti-Hipertensivos/química , Caseínas/química , Bovinos , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Simulação de Dinâmica Molecular , Naloxona/administração & dosagem , Peptídeos/química , Ratos , Ratos Endogâmicos SHR , Receptores Opioides/química , Receptores Opioides/genéticaRESUMO
The use of multitarget drugs has evolved as an alternative to "magic bullets" for the treatment of complex diseases such as cancer, in order to affect simultaneously several targets relevant to the disease. We have designed and synthesized a series of dual agents as both Eg5 inhibitors and calcium channel blockers, bearing a 4-aryldihydropyrimidine core. Compound 2 (aryl: 3-nitrophenyl) was selected as potential dual agent due to displaying both activities: it is a vasorelaxant agent (>90% relaxation at 10-5 M in KCl-precontracted aorta rings), it decreases the response to calcium and it is cytotoxic to MCF-7 (breast), HCT-116 (colon) and A-549 (lung) cancer cell lines. The dual mechanism of action was confirmed by blocking (-)-BAY K8644-induced vascular contraction and production of monopolar spindles, typical of Eg5 inhibition. Docking suggests that both (R) and (S)-enantiomers could bind Eg5.
