Showing papers by "ACADIA Pharmaceuticals Inc. published in 2011"

Pimavanserin, a 5-HT2A inverse agonist, reverses psychosis-like behaviors in a rodent model of Parkinson's disease.

Abstract: Parkinson's disease psychosis (PDP) is a condition for which a safe, tolerated, and effective therapy is lacking. Treatment with typical or atypical antipsychotics may be contraindicated in patients with PDP because of the potential for aggravating motor symptoms. This study used a novel animal model with features of both Parkinson's disease (PD) and psychosis to examine a potential mechanism for reversing PDP. Animals with bilateral 6-hydroxydopamine lesions of the substantia nigra displayed motoric impairments characteristic of humans with PD. In addition, they displayed augmented head twitches, augmented amphetamine-induced locomotor activity, and disrupted prepulse inhibition compared with sham controls, behavioral indices frequently used to assess antipsychotic activity in animal models. Pimavanserin, a selective 5-HT2A antagonist/inverse agonist, reversed the psychotic-like behavioral deficits, suggesting that nigrostriatal (6-hydroxydopamine) lesions induced alterations in 5-HT2A-mediated signaling. The selective 5-HT2A inverse agonist M100907, but not the selective 5-HT2C inverse agonist SB 252084 paralleled the effects of pimavanserin. Of note, the reversal of psychotic-like behaviors produced by 5-HT2A inverse agonists occurred without disrupting motor behaviors in lesioned subjects, suggesting that 5HT2A antagonism/inverse agonism may be beneficial in the treatment of PDP.

Reactions between Grignard reagents and heterocyclic N-oxides: Stereoselective synthesis of substituted pyridines, piperidines, and piperazines

Abstract: In this perspective we discuss the recent developments of stereoselective synthesis of substituted pyridines, piperidines, and piperazines from cheap and commercially readily available starting materials. Pyridine N-oxides and pyrazine N-oxides are reacted with alkyl, aryl, alkynyl and vinyl Grignard reagents to give a diverse set of heterocycles in high yields. Optically active substituted piperazines are obtained by an asymmetric reaction from pyrazine N-oxides using sparteine as chiral ligand. In addition, a stereoselective synthesis of dienal-oximes from the reaction between pyridine N-oxides and Grignard reagents is presented, which results in a useful intermediate for the synthesis of a diverse set of compounds.

Characterization of Highly Efficacious Allosteric Agonists of the Human Calcium-Sensing Receptor

Abstract: We discovered structurally novel human calcium-sensing receptor (CaSR) allosteric agonists and compared their pharmacology to phenylalkylamine calcimimetics. 1-Benzothiazol-2-yl-1-(2,4-dimethyl-phenyl)-ethanol (AC-265347) activated CaSR signaling in cellular proliferation and phosphatidylinositol (PI) hydrolysis assays with potencies of 30 and 10 nM, respectively. (S)-1-Benzothiazol-2-yl-1-(2,4-dimethyl-phenyl)-ethanol) [(S)-AC-265347], the S-enantiomer of AC-265347, was approximately 10- to 20-fold more potent than (R)-1-benzothiazol-2-yl-1-(2,4-dimethyl-phenyl)-ethanol) [(R)-AC-265347]. The phenylalkylamines cinacalcet and calindol had activity similar to that of AC-265347 in cellular proliferation assays but less activity in PI assays. All compounds had reduced activity when extracellular Ca(2+) was removed, indicating that they cooperate with Ca(2+) to activate CaSRs, and all activated CaSR isoforms with the N-terminal extracellular domain deleted, indicating that they interact with the transmembrane domains. In both cases, AC-265347 and therefore (S)-AC-265347 were significantly more efficacious than the phenylalkylamines. Mutations E837A(7.39) and I841A(7.43) strongly reduced phenylalkylamine-induced signaling, but not AC-265347- or (S)-AC-265347-induced signaling, suggesting different modes of binding. AC-265347 and (S)-AC-265347 stimulated significantly greater responses than cinacalcet or calindol at each of four loss-of-function human polymorphic CaSR variants. AC-265347 did not inhibit the CYP2D6 cytochrome P450 isozyme, unlike cinacalcet, which is a potent CYP2D6 inhibitor. In rats, AC-265347, (S)-AC-265347, and (R)-AC-265347 each reduced serum parathyroid hormone (PTH) with a rank order potency correlated with their in vitro potencies. AC-265347 and (S)-AC-265347 also reduced plasma ionizable calcium ([Ca(2+)](o)). AC-265347 was orally active, and its plasma concentrations correlated well with its effects on serum PTH. Thus, these highly efficacious CaSR allosteric agonists represent leads for developing therapeutic agents with potential advantages over existing therapies.

I. In vivo evidence for partial agonist effects of (-)-OSU6162 and (+)-OSU6162 on 5-HT2A serotonin receptors.

Abstract: The locomotor effects of (-)- and (+)-OSU6162 were evaluated in 'low activity' animals (reserpinized mice and habituated rats) and 'high activity' animals (drug-naive mice and non-habituated rats). Both enantiomers of OSU6162 had dual effects on behavior, stimulating locomotor activity in 'low activity' animals and inhibiting locomotor activity in 'high activity' animals. There were also certain differences between the two enantiomers in their behavioral profiles. The stimulatory effects of both enantiomers in reserpinized mice were blocked by the 5-HT2A selective antagonist M100907, but not by the D2-selective antagonists haloperidol or raclopride, or by the D1-selective antagonists SCH23390 or SCH39166. The stimulatory effect in mice was more pronounced for (+)- than for (-)-OSU6162. In drug-naive mice, both enantiomers of OSU6162 produced head twitches, albeit to a much lesser extent than DOI, and both enantiomers inhibited DOI-induced head twitches, the (-)-form more effectively so than the (+)-form. These results suggest that (-)- and (+)-OSU6162 are partial agonists on 5-HT2A receptors and that the (+)-form has a higher intrinsic activity than the (-)-form. At high doses, both enantiomers inhibited locomotor activity in drug-naive mice, with (-)-OSU6162 being more potent than (+)-OSU6162. Similarly, in high-active rats, both enantiomers inhibited locomotor activity, with the (-)-enantiomer being more potent than the (+)-enantiomer. Conversely, in habituated rats, both enantiomers stimulated locomotor activity, and here, as opposed to the case in low-active mice, (-)-OSU6162 was more effective than (+)-OSU6162. The stimulatory effects in habituated rats of both enantiomers could be antagonized with either haloperidol or M100907. Overall, these results indicate that the dual effects on behavior of (-)- and (+)-OSU6162 are mediated through D2 and 5-HT2A receptors, consistent with their in vitro functional selectivity profiles (see Burstein et al., accompanying paper). Thus, both enantiomers of OSU6162 seem to act as stabilizers not only on dopaminergic, but also on serotonergic brain signaling. These discoveries have important implications for the potential clinical utility of both compounds, as well as for several of their congeners.

II. In vitro evidence that (−)-OSU6162 and (+)-OSU6162 produce their behavioral effects through 5-HT2A serotonin and D2 dopamine receptors

Abstract: (−)-OSU6162 has promise for treating Parkinson’s disease, Huntington’s disease and schizophrenia. Behavioral tests evaluating the locomotor effects of (−) and (+)-OSU6162 on ‘low activity’ animals (reserpinized mice and habituated rats) and ‘high activity’ animals (drug naive mice and non-habituated rats) revealed that both enantiomers of OSU6162 had dual effects on behavior, stimulating locomotor activity in ‘low activity’ animals and inhibiting locomotor activity in ‘high activity’ animals. To elucidate a plausible mechanism of action for their behavioral effects, we evaluated the intrinsic actions of (−)- and (+)-OSU6162, and a collection of other antipsychotic and antiparkinsonian agents at 5-HT2A and D2 receptors in functional assays with various degrees of receptor reserve, including cellular proliferation, phosphatidyl inositol hydrolysis, GTPγS and beta-arrestin recruitment assays. We also tested for possible allosteric actions of (−)-OSU6162 at D2 receptors. Both enantiomers of OSU6162 were medium intrinsic activity partial agonists at 5-HT2A receptors and low intrinsic activity partial agonists at D2 receptors. (+)-OSU6162 had higher efficacy at 5-HT2A receptors, which correlated with its greater stimulatory activity in vivo, but (−)-OSU6162 had higher potency at D2 receptors, which correlated with its greater inhibitory activity in vivo. (−)-OSU6162 did not display any convincing allosteric properties. Both (+)- and (−)-OSU6162 were significantly less active at 27 other monoaminergic receptors and reuptake transporters tested suggesting that D2 and 5-HT2A receptors play crucial roles in mediating their behavioral effects. Compounds with balanced effects on these two receptor systems may offer promise for treating neuropsychiatric diseases.

Can alpha-synuclein be targeted in novel therapies for Parkinson's disease?

Abstract: Classical descriptions of the symptoms of Parkinson’s disease (PD) focus on the progressive development of rigidity, tremor and hypokinesia. However, patients also suffer from a range of debilitati...