receptors and potently antagonized R(ϩ)-2-dipropylamino-7-hydroxy-1,2,3,4-tetra-hydronaphtalene HBr (7-OH-DPAT)-induced suppression of cAMP formation (pK b 9.57). In these functional assays, cariprazine showed similar (D 2 ) or higher (D 3 ) antagonist-partial agonist affinity and greater (3-to 10-fold) D 3 versus D 2 selectivity compared with aripiprazole. In in vivo turnover and biosynthesis experiments, cariprazine demonstrated D 2 -related partial agonist and antagonist properties, depending on actual dopaminergic tone. The antagonist-partial agonist properties of cariprazine at D 3 and D 2 receptors, with very high and preferential affinity to D 3 receptors, make it a candidate antipsychotic with a unique pharmacological profile among known antipsychotics. Dopamine D 3 receptors, cloned in the beginning of the 1990s (Sokoloff et al., 1990), are most abundant in the mesolimbic regions (i.e., nucleus accumbens, island of Calleja) where dysregulation of neurotransmission is thought to be associated with psychosis. The discovery that most antipsychotics, in addition to binding to D 2 receptors, display reasonably high affinity for D 3 receptors, led to the assumption that these receptors may also be responsible for antipsychotic efficacy (Sokoloff et al., 1995). Unfortunately, the selective D 3Article, publication date, and citation information can be found at

The adverse effects of heat on plant yield strongly depend on its duration and the phenological stage of the crops when the heat occurs. To clarify the effects of these two aspects of heat stress, systematic research was conducted under controlled conditions on 101 wheat cultivars of various geographic origin. Different durations of heat stress (5, 10 and 15 days) were applied starting from three developmental stages (ZD49: booting stage, ZD59: heading, ZD72: 6th day after heading). Various morphological, yield-related traits and physiological parameters were measured to determine the stress response patterns of the wheat genotypes under combinations of the duration and the timing of heat stress. Phenological timing significantly influenced the thousand-kernel weight and reproductive tiller number. The duration of heat stress was the most significant component in determining both seed number and seed weight, as well as the grain yield consequently, explaining 51.6% of its phenotypic variance. Irrespective of the developmental phase, the yield-related traits gradually deteriorated over time, and even a 5-day heat stress was sufficient to cause significant reductions. ZD59 was significantly more sensitive to heat than either ZD49 or ZD72. The photosynthetic activity of the flag leaf was mostly determined by heat stress duration. No significant associations were noted between physiological parameters and heat stress response as measured by grain yield. Significant differences were observed between the wheat genotypes in heat stress responses, which varied greatly with developmental phase. Based on the grain yield across developmental phases and heat stress treatments, eight major response groups of wheat genotypes could be identified, and among them, three clusters were the most heat-tolerant. These cultivars are currently included in crossing schemes, partially for the identification of the genetic determinants of heat stress response and partially for the development of new wheat varieties with better heat tolerance.

Palladium(II)-catalyzed intramolecular 1,2-additions to allenes substituted with an internal nucleophile have been developed. Carboxylic acids, alcohols, N-substituted amides, and carbamates were used as internal nucleophiles in the palladium-catalyzed reaction, which afforded lactones, tetrahydropyrans, tetrahydrofurans, pyrrolidines, and oxazolidinones in good isolated yields. The reactions were performed in the presence of LiBr with Pd(OAc) 2 as the catalyst. Two different reoxidants, p-benzoquinone or Cu(OAc) 2 , were used, the choice of oxidant being dependent on the substrate. The reaction proceeds through an external nucleophilic attack (Br -) on a (π-allene)palladium complex to produce a (π-allyl)palladium intermediate. Subsequent intramolecular attack by the second internal nucleophile gives the product. The intermediate (π-allyl)palladium complexes were isolated and characterized. The scope and limitation of the reaction were studied together with its mechanism and selectivity, under different reaction conditions.

Dopamine D 3 receptor partial agonism has been suggested as a potential therapeutic intervention in cocaine addiction. )-piperazin-1-yl]-butyl}-4-bromo-benzamide] was identified as a novel selective dopamine D 3 receptor partial agonist and used for testing this hypothesis in animal models. The compound showed nanomolar affinity to human (K i ϭ 6.7 nM) and rat (K i ϭ 1.6 nM) D 3 receptors with an intrinsic activity of approximately 50%. It possessed several hundredfold selectivity over the D 2 receptor. The molecule bound with moderate (100 -250 nM) affinity to 5-hydroxytryptamine 1A (5-HT 1A ) and nonselectively labeled opiate receptors. RGH-237 proved to be practically inactive on more than 40 other targets, including monoaminergic, cholinergic, GABAergic, and glutamatergic receptors. In rats orally administered RGH-237 was well and rapidly absorbed yielding 41% oral bioavailability. At its pharmacologically active dose (10 mg/kg p.o.), the brain concentration of RGH-237 reached 110 ng/g. Its blood and brain levels were sustained for 3 h. RGH-237 at the oral dose of 10 mg/kg moderately but significantly inhibited the acquisition of cocaine-induced place preference, although by itself, it had no place-conditioning effect. The compound did not affect fixed ratio 1 cocaine self-administration. In a reinstatement paradigm of cocaine self-administration, the compound potently and dose-dependently blocked the cue-induced cocaine-seeking behavior of rats at 10 and 30 mg/kg oral doses. RGH-237 did not affect seeking activity for natural rewards, such as sucrose and water. It did not exert notable effect on spontaneous motor activity of rats. Our results demonstrate that selective D 3 partial agonists may be an effective therapeutic means in the treatment of cocaine abuse.In recent years, a growing body of evidence has accumulated from animal studies demonstrating the importance of dopamine D 3 receptors in mechanisms of cocaine addiction. Nonselective D 2 -like dopaminergic agonists were shown to mimic the effects of cocaine in drug discrimination (Spealman, 1996) as well as in cocaine self-administration paradigms (Caine et al., 1997, Parsons et al., 1996, and the order of potency of the compounds highly correlated with their in vitro affinity and functional activity on D 3 but not on D 2 receptors (Spealman, 1996;Caine et al., 1997). In addition, nafadotride, a modestly selective D 3 receptor antagonist (Sautel et al., 1995), decreased the reinforcing effect of cocaine in the latter method (Caine et al., 1997). Furthermore, the partial D 3 agonist compound BP-897 (Pilla et al., 1999) and the highly selective D 3 full antagonist SB-277011-A (Reavill et al., 2000) were reported to decrease cue-induced drug seeking under a second-order schedule of cocaine selfadministration (Pilla et al., 1999;Di Ciano et al., 2003).More important and clinically more relevant are the findings obtained with dopamine D 3 receptor ligands in various paradigms of reinstatement of cocaine seeking, which model Article, publication ...

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Rationale Cariprazine is a novel antipsychotic drug candidate that exhibits high selectivity and affinity to dopamine D3 and D2 receptors and moderate affinity to serotonin 5-HT1A receptors. Targeting receptors other than D2 may provide a therapeutic benefit for both positive and negative symptoms associated with schizophrenia. Positron emission tomography (PET) can be used as a tool in drug development to assess the in vivo distribution and pharmacological properties of a drug. Objectives The objective of this study was to determine dopamine D2/D3 and serotonin 5-HT1A receptor occupancy in monkey brain after the administration of cariprazine. Methods We examined three monkeys using the following PET radioligands: [11C]MNPA (an agonist at D2 and D3 receptors), [11C]raclopride (an antagonist at D2 and D3 receptors), and [11C]WAY-100635 (an antagonist at 5-HT1A receptors). During each experimental day, the first PET measurement was a baseline study, the second after a low dose of cariprazine, and the third after the administration of a high dose. Results We found that cariprazine occupied D2/D3 receptors in a dose-dependent and saturable manner, with the lowest dose occupying ~5% of receptors and the highest dose showing more than 90% occupancy. 5-HT1A receptor occupancy was considerably lower compared with D2/D3 occupancy at the same doses, with a maximal value of ~30% for the raphe nuclei. Conclusions We conclude that cariprazine binds preferentially to dopamine D2/D3 rather than to serotonin 5-HT1A receptors in monkey brain. These findings can be used to guide the selection of cariprazine dosing in humans.

Allenes undergo racemization in the presence of catalytic amounts of Pd(OAc)2/LiBr under mild conditions; the reaction proceeds via a bromopalladation-debromopalladation sequence and tolerates various functional groups.

The reaction of acetylated alpha-allenic alcohols with LiBr in the presence of 1.5 mol % of Pd(OAc)(2) provides easy access to substituted (Z,E)-2-bromo-1,3-dienes in good yields with excellent diastereoselectivity. Both secondary and tertiary acetates as well as terminal and nonterminal allenes were studied to investigate the scope and the limitations of the reaction. A mechanism is proposed to clarify how a diastereomeric mixture of the starting compound is transformed into a single diastereomer of the product.