Pharmacology of JNJ-37822681, a specific and fast-dissociating D2 antagonist for the treatment of schizophrenia.

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.

Synthesis, structure-activity relationship, and receptor pharmacology of a new series of quinoline derivatives acting as selective, noncompetitive mGlu1 antagonists.

We describe the discovery and the structure-activity relationship of a new series of quinoline derivatives acting as selective and highly potent noncompetitive mGlu1 antagonists. We first identified cis-10 as a fairly potent mGlu1 antagonist (IC(50) = 20 nM) in a cell-based signal transduction assay on the rat mGlu1 receptor expressed in CHO-K1 cells, and then we were able to design and synthesize highly potent compounds on both rat and human mGlu1 receptors as exemplified by compound cis-64a, which has an antagonist potency of 0.5 nM for the human mGlu1 receptor. We briefly present and discuss the in vitro metabolic stability of the compounds in human liver microsomes. We finally report the pharmacokinetic properties of our lead compound cis-64a.

JNJ16259685, a highly potent, selective and systemically active mGlu1 receptor antagonist.

We examined the pharmacological profile of (3,4-dihydro-2H-pyrano[2,3]b quinolin-7-yl) (cis-4-methoxycyclohexyl) methanone (JNJ16259685). At recombinant rat and human metabotropic glutamate (mGlu) 1a receptors, JNJ16259685 non-competitively inhibited glutamate-induced Ca2+ mobilization with IC50 values of 3.24+/-1.00 and 1.21+/-0.53 nM, respectively, while showing a much lower potency at the rat and human mGlu5a receptor. JNJ16259685 inhibited [3H]1-(3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-phenyl-1-ethanone ([3H]R214127) binding to membranes prepared from cells expressing rat mGlu1a receptors with a Ki of 0.34+/-0.20 nM. JNJ16259685 showed no agonist, antagonist or positive allosteric activity toward rat mGlu2, -3, -4 or -6 receptors at concentrations up to 10 microM and did not bind to AMPA or NMDA receptors, or to a battery of other neurotransmitter receptors, ion channels and transporters. In primary cerebellar cultures, JNJ16259685 inhibited glutamate-mediated inositol phosphate production with an IC50 of 1.73+/-0.40 nM. Subcutaneously administered JNJ16259685 exhibited high potencies in occupying central mGlu1 receptors in the rat cerebellum and thalamus ( ED50=0.040 and 0.014 mg/kg, respectively). These data show that JNJ16259685 is a selective mGlu1 receptor antagonist with excellent potencies in inhibiting mGlu1 receptor function and binding and in occupying the mGlu1 receptor after systemic administration.

Synthesis and biological activities of conformationally restricted cyclopentenyl-glutamate analogues.

An efficient method for preparing conformationally restricted cyclopentenyl-glutamate analogues in a regioselective and diastereoselective manner has been developed using a formal [3 + 2] cycloaddition reaction of dehydroamino acids. Methods for preparing optically active versions of these compounds have also been devised. Of these compounds, (S)-2 is an agonist at the mGlu5 (EC(50) 18 microM) and mGlu2 (EC(50) 45 microM) receptors.