Linear free-energy relationships in series of alkanolamines as lysosomotropic agents and choline uptake inhibitors

The solvation parameters model was used to develop a series of statistically significant linear free-energy relationship [LFER] associating lipophilicity [expressed as the logarithm of partition coefficients in n-octanol/water system, log P oct] of 25 diverse alkanolamines with their five structural descriptors constituting the general solvation parameters model proposed by Abraham [1989], as V x, the McGowan [1987] characteristic volume R 2, the excess of molar refraction [PI] H, the dipolarity/polarizability, sigma alpha H, the hydrogen-bond acidity, and sigma beta H, the effective hydrogen-bond basicity. A modified set of the fragmental constants for estimation of PI H, sigma alpha H, and sigma beta H, descriptors of individual alkanolamines has been proposed and applied to calculations of LFER by the multivariate regression procedure. Similary, LFER were established for the experimental values of logarithms of reciprocal of the minimal bactericidal concentration [log[1/MBC]] in a series of lysosomotropic alkabikanubes as reported by Sandin et al. [1992]. The calculated LFER model demonstrates that molecular size [V x term] and effective hydrogen-bond acidity [sigma alpha H term] are the most important structural parameters favouring the transport of uncharged forms of alkanolamines through the bacterial cytoplasmic membrane and their accumulation in bacterial cells. The LFER approach was also applied to experimental data relating 14 alkanolamines as the inhibitors of choline uptake into murine L1210 leukemia cells reported by Naujokaitis et al. [1984]. In this case the established LFER shows that the crucial factors which determine the inhibition of choline transport by alkanolamines are specific dispersion interactions [R 2 term], molecular size [V x term] and effective hydrogen-bond basicity [sigma beta H term] that decreases observed inhibition. The results of the studies presented indicate LFER as a suitable method for the pre-selection of the alkanolamines with defined molecular characteristics for the in vivo chemotherapy of lymphocytic leukemia

Central injection of captopril inhibits the blood pressure response to intracerebroventricular choline

In the present study, we investigated the involvement of the brain renin-angiotensin system in the effects of central cholinergic stimulation on blood pressure in conscious, freely moving normotensive rats. In the first step, we determined the effects of intracerebroventricular (icv) choline (50, 100 and 150 µg) on blood pressure. Choline increased blood pressure in a dose-dependent manner. In order to investigate the effects of brain renin-angiotensin system blockade on blood pressure increase induced by choline (150 µg, icv), an angiotensin-converting enzyme inhibitor, captopril (25 and 50 µg, icv), was administered 3 min before choline. Twenty-five µg captopril did not block the pressor effect of choline, while 50 µg captopril blocked it significantly. Our results suggest that the central renin-angiotensin system may participate in the increase in blood pressure induced by icv choline in normotensive rats.

Crotoxin, the major toxin from the rattlesnake Crotalus durissus terrificus, inhibits 3H-choline uptake in guinea pig ileum

We examined the effect of crotoxin, the neurotoxic complex from the venom of the South American rattlesnake Crotalus durissus terrificus, on the uptake of 3H-choline in minces of smooth muscle myenteric plexus from guinea pig ileum. In the concentration range used (0.03-1 ÁM) and up to 10 min of treatment, crotoxin decreased 3H-choline uptake by 50-75 percent compared to control. This inhibition was time dependent and did not seem to be associated with the disruption of the neuronal membrane, because at least for the first 20 min of tissue exposure to the toxin (up to 1 ÁM) the levels of lactate dehydrogenase (LDH) released into the supernatant were similar to those of controls. Higher concentrations of crotoxin or more extensive incubation times with this toxin resulted in elevation of LDH activity detected in the assay supernatant. The inhibitory effect of crotoxin on 3H-choline uptake seems to be associated with its phospholipase activity since the equimolar substitution of Sr2+ for Ca2+ in the incubation medium or the modification of the toxin with p-bromophenacyl bromide substantially decreased this effect. Our results show that crotoxin inhibits 3H-choline uptake with high affinity (EC25 = 10 +/- 5 nM). We suggest that this inhibition could explain, at least in part, the blocking effect of crotoxin on neurotransmission