Description: Preeclampsia is associated with a 4-fold higher risk for developing remote chronic hypertension. Preeclampsia is accompanied by left ventricular hypertrophy and decreased diastolic function, which may or may not resolve postpartum. We tested the hypothesis that increased measures of cardiac geometry and decreased cardiac function persisting for ≥6 months postpartum in normotensive women with a history of preeclampsia precede the development of later chronic hypertension. Formerly preeclamptic women (n=652) underwent echocardiography at 9 months (range, 6–19) postpartum. We excluded women with preexisting hypertension (n=42), hypertension at the postpartum screening (n=133), and those that did not return any checklist (n=128). Eventually, 349 women were included. Remote health was evaluated by a biennially checklist. We used Cox regression for analysis. Twenty-seven (8%) normotensive women had developed chronic hypertension during a medium follow-up period of 6 years. At screening they differed from their counterparts who remained normotensive by hazard ratio for left ventricular mass index (1.11; 95% confidence interval [CI], 1.03–1.18), diastolic blood pressure (1.13; 95% CI, 1.06–1.20), systolic blood pressure (1.07; 95% CI, 1.02–1.11), mean arterial pressure (1.11; 95% CI, 1.05–1.18), heart rate (1.05; 95% CI, 1.01–1.10), and E/A ratio (0.22; 95% CI, 0.06–0.85). Backward stepwise analysis showed independent hazard ratio for left ventricular mass index and diastolic blood pressure 1.08 (95% CI, 1.01–1.16) and 1.13 (95% CI, 1.06–1.21), respectively. In conclusion, the development of later chronic hypertension in initially normotensive formerly preeclamptic women is preceded by increased left ventricular mass index and diastolic blood pressure at postpartum screening.

Description: All marketed antipsychotics act by blocking dopamine D 2 receptors. Fast dissociation from D 2 receptors may be one of the elements contributing to the lower incidence of extrapyramidal symptoms (EPS) exhibited by newer antipsychotics. Therefore, we screened for specific D 2 receptor blockers with a fast rate of dissociation. Radioligand binding experiments identified N- [1-(3,4-difluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (JNJ-37822681) as a fast-dissociating D 2 ligand. Its D 2 receptor specificity was high compared with atypical antipsychotics, with little activity at receptors associated with unwanted effects [α 1 , α 2 , H 1 , muscarinic, and 5-hydroxytryptamine (5-HT) type 2C] and for receptors that may interfere with the effects of D 2 antagonism (D 1 , D 3 , and 5-HT 2A ). JNJ-37822681 occupied D 2 receptors in rat brain at relatively low doses (ED 50 0.39 mg/kg) and was effective in animal models of psychosis (e.g., inhibition of apomorphine-induced stereotypy or d -amphetamine/phencyclidine-induced hyperlocomotion). Prolactin levels increased from an ED 50 (0.17 mg/kg, peripheral D 2 receptors) close to the ED 50 required for apomorphine antagonism (0.19 mg/kg, central D 2 receptors), suggesting excellent brain disposition and minimal prolactin release at therapeutic doses. JNJ-37822681 induced catalepsy and inhibited avoidance behavior, but with a specificity margin relative to apomorphine antagonism that was larger than that obtained for haloperidol and similar to that obtained for olanzapine. This larger specificity margin (compared with haloperidol) may reflect lower EPS liability and less behavioral suppression after JNJ-37822681. JNJ-37822681 is a novel, potent, specific, centrally active, fast-dissociating D 2 antagonist with optimal brain disposition, and it is the first compound that allows the evaluation of the potential value of fast D 2 antagonism for the treatment of schizophrenia and bipolar disorder.

Description: Modulation of the metabotropic glutamate type 2 (mGlu2) receptor is considered a promising target for the treatment of central nervous system diseases such as schizophrenia. Here, we describe the pharmacological properties of the novel mGlu2 receptor positive allosteric modulator (PAM) 3-cyano-1-cyclopropylmethyl-4-(4-phenyl-piperidin-1-yl)-pyridine-2(1 H )-one (JNJ-40068782) and its radioligand [ 3 H]JNJ-40068782. In guanosine 5'- O -(3-[ 35 S]thio)triphosphate binding, JNJ-40068782 produced a leftward and upward shift in the glutamate concentration-effect curve at human recombinant mGlu2 receptors. The EC 50 of JNJ-40068782 for potentiation of an EC 20 -equivalent concentration of glutamate was 143 nM. Although JNJ-40068782 did not affect binding of the orthosteric antagonist [ 3 H]2 S -2-amino-2-(1 S ,2 S -2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid (LY-341495), it did potentiate the binding of the agonist [ 3 H](2 S ,2' R ,3' R )-2-(2',3'-dicarboxylcyclopropyl)glycine (DCG-IV), demonstrating that it can allosterically affect binding at the agonist recognition site. The binding of [ 3 H]JNJ-40068782 to human recombinant mGlu2 receptors in Chinese hamster ovary cells and rat brain receptors was saturable with a K D of ~10 nM. In rat brain, the anatomic distribution of [ 3 H]JNJ-40068782 was consistent with mGlu2 expression previously described and was most abundant in cortex and hippocampus. The ability of structurally unrelated PAMs to displace [ 3 H]JNJ-40068782 suggests that PAMs may bind to common determinants within the same site. It is noteworthy that agonists also increased the binding affinity of [ 3 H]JNJ-40068782. JNJ-40068782 influenced rat sleep-wake organization by decreasing rapid eye movement sleep with a lowest active dose of 3 mg/kg PO. In mice, JNJ-40068782 reversed phencyclidine-induced hyperlocomotion with an ED 50 of 5.7 mg/kg s.c. Collectively, the present data demonstrate that JNJ-40068782 has utility in investigating the potential of mGlu2 modulation for the treatment of diseases characterized by disturbed glutamatergic signaling and highlight the value of [ 3 H]JNJ-40068782 in exploring allosteric binding.