Mapping antimalarial pharmacophores as a useful tool for the rapid discovery of drugs effective in vivo: design, construction, characterization, and pharmacology of metaquine

Resistant strains of Plasmodium falciparum and the unavailability of useful antimalarial vaccines reinforce the need to develop new efficacious antimalarials. This study details a pharmacophore model that has been used to identify a potent, soluble, orally bioavailable antimalarial bisquinoline, metaquine (N,N'-bis(7-chloroquinolin-4-yl)benzene-1,3-diamine) (dihydrochloride), which is active against Plasmodium berghei in vivo (oral ID50 of 25 mu mol/kg) and multidrug-resistant Plasmodium falciparum K1 in vitro (0.17 mu M). Metaquine shows strong affinity for the putative antimalarial receptor, heme at pH 7.4 in aqueous DMSO. Both crystallographic analyses and quantum mechanical calculations (HF/6-31+G*) reveal important regions of protonation and bonding thought to persist at parasitic vacuolar pH concordant with our receptor model. Formation of drug-heme adduct in solution was confirmed using high-resolution positive ion electrospray mass spectrometry. Metaquine showed strong binding with the receptor in a 1: 1 ratio (log K = 5.7 +/- 0.1) that was predicted by molecular mechanics calculations. This study illustrates a rational multidisciplinary approach for the development of new 4-aminoquinoline antimalarials, with efficacy superior to chloroquine, based on the use of a pharmacophore model.

Effects of trauma exposure on the cortisol response to dexamethasone administration in PTSD and major depressive disorder

Objective: To evaluate cortisol suppression following 0.5 mg of dexamethasone (DEX) in trauma survivors (N = 52),with posttraumatic stress disorder (PTSD), major depressive disorder (MDD), both, or neither disorder, and in subjects never exposed to trauma (N = 10), in order to examine interactions between diagnosis and trauma history on cortisol negative feedback inhibition. Method: Lifetime trauma exposure and psychiatric diagnoses were assessed and blood samples were obtained at 8:00 a.m. for the determination of baseline cortisol. Participants ingested 0.5 mg of DEX at 11:00 p.m. and blood samples for determination of cortisol and DEX were obtained at 8:00 a.m. the following day. Results: PTSD was associated with enhanced cortisol suppression in response to DEX Among trauma survivors, the presence of a traumatic event prior to the "focal" trauma had a substantial impact on cortisol suppression in subjects with MDD. Such subjects were more likely to show cortisol alterations similar to those associated with PTSD, whereas subjects with MDD with no prior trauma were more likely to show alterations in the opposite direction, i.e. relative non-suppression. Conclusions: Cortisol hypersuppression in PTSD appears not to be dependent on the presence of traumatic events prior to the focal trauma. However, prior trauma exposure may affect cortisol suppression in MDD. This finding may have implications for understanding why only some depressed patients show non-suppression on the DST. Published by Elsevier Ltd.

The ACTH response to dexamethasone in PTSD

Objective: Enhanced negative feedback and reduced adrenal output are two different models that have been put forth to explain the paradoxical observations of increased release of corticotropin-releasing factor in the face of low cortisol levels in posttraumatic stress disorder (PTSID). To discriminate between these models, the authors measured levels of adrenocorticopic hormone (ACTH) and cortisol at baseline and in response to dexamethasone in medically healthy subjects with and without PTSID. Under conditions of enhanced negative feedback inhibition, ACTH levels would not be altered relative to cortisol levels, but the ACTH response to dexamethasone would be augmented, in concert with the enhanced cortisol response to dexamethasone. In contrast, under conditions of reduced adrenal output, ACTH levels would be expected to be higher at baseline relative to cortisol levels, but the ACTH response to dexamethasone would be unchanged in PTSID relative to healthy comparison subjects. Method: The ACTH and cortisol responses to 0.50 mg of dexamethasone were assessed in 19 subjects (15 men and four women) with PTSID and 19 subjects (14 men and five women) without psychiatric disorder. Results: The ACTH-to-cortisol ratio did not differ between groups before or after dexamethasone, but the subjects with PTSD showed greater suppression of ACTH (as well as cortisol) in response to dexamethasone. Conclusions: The data support the hypothesis of enhanced cortisol negative feedback inhibition of ACTH secretion at the level of the pituitary in PTSD. Pituitary glucocorticoid receptor binding, rather than low adrenal output, is implicated as a likely mechanism for this effect.