Implication of Opioid Receptors in the Antihypertensive Effect of a Bovine Casein Hydrolysate and αs1-Casein-Derived Peptides.

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.

Dihydropyrimidine-2-thiones as Eg5 inhibitors and L-type calcium channel blockers: potential antitumour dual agents.

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.

Antinociceptive, brain-penetrating derivatives related to improgan, a non-opioid analgesic.

The antinociceptive profile of selected histamine H(2) and histamine H(3) receptor antagonists led to the discovery of improgan, a non-brain-penetrating analgesic agent which does not act on known histamine receptors. Because no chemical congener of improgan has yet been discovered which has both antinociceptive and brain-penetrating properties, the present study investigated the antinociceptive effects of a series of chemical compounds related to zolantidine, a brain-penetrating histamine H(2) receptor antagonist. The drugs studied presently contain the piperidinomethylphenoxy (PMPO) moiety, hypothesized to introduce brain-penetrating characteristics. Following intracerebroventricular (i.c.v.) dosing in rats, six of eight drugs produced dose- and time-related antinociception on both the tail flick and hot plate tests over a nearly eight-fold range of potencies. Ataxia and other motor side effects were observed after high doses of these drugs, but two of the compounds (SKF94674 and loxtidine) produced maximal antinociception at doses which were completely devoid of these motor effects. Consistent with the hypothesis that PMPO-containing drugs are brain-penetrating analgesics, SKF94674 and another derivative (JB-9322) showed dose-dependent antinociceptive activity 15 to 30 min after systemic dosing in mice, but these effects were accompanied by seizures and death beginning 45 min after dosing. Other drugs showed a similar pattern of antinociceptive and toxic effects. In addition, loxtidine produced seizures without antinociception, whereas zolantidine produced neither effect after systemic dosing in mice. Although several of the drugs tested have histamine H(2) receptor antagonist activity, neither the antinociception nor the toxicity was correlated with histamine H(2) receptor activity. The present results are the first to demonstrate the existence of brain-penetrating antinociceptive agents chemically related to zolantidine and improgan, but further studies are needed to understand the mechanisms of both the pain relief and toxicity produced by these agents.