Aripiprazole is the first next-generation atypical antipsychotic with a mechanism of action that differs from currently marketed typical and atypical antipsychotics. Aripiprazole displays properties of an agonist and antagonist in animal models of dopaminergic hypoactivity and hyperactivity, respectively. This study examined the interactions of aripiprazole with a single population of human D2 receptors to clarify further its pharmacologic properties. In membranes prepared from Chinese hamster ovary cells that express recombinant D2L receptors, aripiprazole bound with high affinity to both the G protein-coupled and uncoupled states of receptors. Aripiprazole potently activated D2 receptor-mediated inhibition of cAMP accumulation. Partial receptor inactivation using the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) significantly reduced the maximum effect of aripiprazole on inhibition of cAMP accumulation. This effect was seen with concentrations of EEDQ that did not alter the maximal inhibitory effect of dopamine. Consistent with the expected effects of a partial agonist, increasing concentrations of aripiprazole blocked the action of dopamine with maximal blockade equal to the agonist effect of aripiprazole alone. The efficacy of aripiprazole relative to that of dopamine varied from 25% in cells that lacked spare receptors for dopamine to 90% in cells with receptor reserve. These results, together with previous studies demonstrating partial agonist activity at serotonin 5-hydroxytryptamine (5-HT)1A receptors and antagonist activity at 5-HT2A receptors, support the identification of aripiprazole as a dopamine-serotonin system stabilizer. The receptor activity profile may underlie the unique activity of aripiprazole in animals and its antipsychotic activity in humans.
Therapeutic agents that block the calcitonin gene-related peptide (CGRP) signaling pathway are a highly anticipated and promising new drug class for migraine therapy, especially after reports that small-molecule CGRP-receptor antagonists are efficacious for both acute migraine treatment and migraine prevention. Using XenoMouse technology, we successfully generated AMG 334, a fully human monoclonal antibody against the CGRP receptor. Here we show that AMG 334 competes with [ 125 I]-CGRP binding to the human CGRP receptor, with a K i of 0.02 nM. AMG 334 fully inhibited CGRP-stimulated cAMP production with an IC 50 of 2.3 nM in cell-based functional assays (human CGRP receptor) and was 5000-fold more selective for the CGRP receptor than other human calcitonin family receptors, including adrenomedullin, calcitonin, and amylin receptors. The potency of AMG 334 at the cynomolgus monkey (cyno) CGRP receptor was similar to that at the human receptor, with an IC 50 of 5.7 nM, but its potency at dog, rabbit, and rat receptors was significantly reduced (.5000-fold). Therefore, in vivo target coverage of AMG 334 was assessed in cynos using the capsaicin-induced increase in dermal blood flow model. AMG 334 dose-dependently prevented capsaicin-induced increases in dermal blood flow on days 2 and 4 postdosing. These results indicate AMG 334 is a potent, selective, full antagonist of the CGRP receptor and show in vivo dose-dependent target coverage in cynos. AMG 334 is currently in clinical development for the prevention of migraine.
Several analogs of the potent dopamine (DA) transporter ligand 4-[2-[bis(4-fluorophenyl)-methoxy]ethyl]-1-(3-phenylpropyl)piperidine, 1b, were made and biologically evaluated for their binding at the DA and serotonin (5HT) transporters in rat striatal membranes. Different alkyl chain lengths and substitutions were introduced in these molecules to generate an optimum activity and selectivity for the DA transporter. In general, unsubstituted and fluoro-substituted compounds were the most active and selective for the DA transporter. The compound 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine, 9a, showed high potency and was the most selective for the DA transporter (5HT/DA = 49) in this series of compounds. Some of these novel analogs were found to be more selective in binding at the DA transporter than the original GBR 12909 molecule, 1-[2-]bis(4-fluorophenyl)methoxy]ethyl]-4-(3- phenylpropyl)piperidine.
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