Medial orbitofrontal cortex dopamine D1/D2 receptors differentially modulate distinct forms of probabilistic decision-making.

Efficient decision-making involves weighing the costs and benefits associated with different actions and outcomes to maximize long-term utility. The medial orbitofrontal cortex (mOFC) has been implicated in guiding choice in situations involving reward uncertainty, as inactivation in rats alters choice involving probabilistic rewards. The mOFC receives considerable dopaminergic input, yet how dopamine (DA) modulates mOFC function has been virtually unexplored. Here, we assessed how mOFC D1 and D2 receptors modulate two forms of reward seeking mediated by this region, probabilistic reversal learning and probabilistic discounting. Separate groups of well-trained rats received intra-mOFC microinfusions of selective D1 or D2 antagonists or agonists prior to task performance. mOFC D1 and D2 blockade had opposing effects on performance during probabilistic reversal learning and probabilistic discounting. D1 blockade impaired, while D2 blockade increased the number of reversals completed, both mediated by changes in errors and negative feedback sensitivity apparent during the initial discrimination of the task, which suggests changes in probabilistic reinforcement learning rather than flexibility. Similarly, D1 blockade reduced, while D2 blockade increased preference for larger/risky rewards. Excess D1 stimulation had no effect on either task, while excessive D2 stimulation impaired probabilistic reversal performance, and reduced both profitable risky choice and overall task engagement. These findings highlight a previously uncharacterized role for mOFC DA, showing that D1 and D2 receptors play dissociable and opposing roles in different forms of reward-related action selection. Elucidating how DA biases behavior in these situations will expand our understanding of the mechanisms regulating optimal and aberrant decision-making.

Synthesis, fungicidal activity, and 3D-QSAR of tetrazole derivatives containing phenyloxadiazole moieties.

In an effort to discover new agents with good fungicidal activities against CDM (cucumber downy mildew), a series of tetrazole derivatives containing phenyloxadiazole moieties were designed and synthesized. The EC50 values for fungicidal activities against CDM were determined. Bioassay results indicated that most synthesized compounds exhibited potential in vivo fungicidal activity against CDM. A CoMFA (comparative molecular field analysis) model based on the bioactivity was developed to identify some primary structural quality for the efficiency. The values of q2 and r2 for the established model were 0.791 and 0.982 respectively, which reliability and predict abilities were verified. Three analogues (q3, q4, q5) were designed and synthesized based on the model. All these compounds exhibited significant fungicidal activity on CDM with the EC50 of 1.43, 1.52, 1.77 mg·L-1. This work could provide a useful instruction for the further structure optimization.

Design, Synthesis, and Structure-Activity Relationship of Economical Triazole Sulfonamide Aryl Derivatives with High Fungicidal Activity.

Plant fungal diseases have caused great decreases in crop quality and yield. As one of the considerable agricultural diseases, cucumber downy mildew (CDM) caused by pseudoperonospora cubensis seriously influences the production of cucumber. Amisulbrom is a commercial agricultural fungicide developed by Nissan Chemical, Ltd., for the control of oomycetes diseases that is highly effective against CDM. However, the synthesis of amisulbrom has a high cost because of the introduction of the bromoindole ring. In addition, the continuous use of amisulbrom might increase the risk of resistance development. Hence, there is an imperative to develop active fungicides with new scaffolds but low cost against CDM. In this study, a series of 1,2,4-triazole-1,3-disulfonamide derivatives were designed, synthesized, and screened. Compound 1j showed a comparable fungicidal activity with amisulbrom, but it was low cost and ecofriendly. It has the potential to be developed as a new fungicide candidate against CDM. Further investigations of structure-activity relationship exhibited the structural requirements of 1,2,4-triazole-1,3-disulfonamide and appropriate modification in N-alkyl benzylamine groups with high fungicidal activity. This research will provide powerful guidance for the design of highly active lead compounds with a novel skeleton and low cost.

Effect of Suo Quan Wan on the bladder function of aging rats based on the ß-adrenoceptor.

Suo Quan Wan (SQW) has been used to treat lower urinary tract symptoms (LUTS) in elderly patients for hundreds of years in China. ß-adrenoceptors (ß-ARs), particularly ß3-adrenoceptor (ß3-AR), was reported to be important in the bladder dysfunction of the elderly. The present study was conducted to explore the effect of ß-AR, and particularly the ß3-adrenoceptor, in aging rat bladder function in vitro and to test the therapeutic effect of SQW on LUTS in an aging rat model based on the ß3-adrenoceptor. Briefly, the bladder detrusor muscles of young (age, 3 months) and aging (age, 15 months) female rats were separated. A ß-AR non-selective agonist, isoprenaline (ISO), subtype ß3-AR agonist (BRL37344A) and ß3-AR antagonist (SR59230A) were used to define the tension change of detrusor muscles between young and aging rats in vitro. For blank controls, 12 young rats were marked, and 48 aging female rats were randomly divided into four groups as follows: Model, SQW high, SQW middle and SQW low. Following oral administration of SQW for 6 weeks in aging rats, urodynamic and bladder detrusor tests were used to evaluate the therapeutic effect of SQW. The expression of ß3-AR mRNA was investigated using reverse transcription-quantitative polymerase chain reaction. Using ISO and BRL37344A in vitro, maximum relaxation (Emax), intrinsic activity (IA), and log (50% effective concentration) (PD2) were significantly decreased in aging rats compared with that in young rats (P<0.05). Significant changes were also observed in the ß3-AR antagonist experiment, which blocked ISO-induced relaxation, with significant decreases observed in Emax, IA and PD2, and a significant increase observed in PA2 for the aging rats compared with the young controls (P<0.05). SQW was demonstrated to enhance bladder control, storage and contraction ability. Furthermore, SQW was able to increase the sensitivity and expression of ß3-AR in an aging rat. In conclusion, the decrease in ß3-AR sensitivity in aging rats and the expression resulted in bladder detrusor dysfunction. In addition, the therapeutic effect of SQW against LUTS relies on the former's effect on the urethral sphincter, bladder detrusor and ß3-AR.

Nanotubular non-covalent macrocycle within non-covalent macrocycle assembly: (MeOH)(12) encapsulated in a molecular clip cyclododecamer.

A noncovalent macrocycle-within-noncovalent macrocycle assembly is formed from twelve molecules of (+/-)-1 and twelve molecules of MeOH in the solid state. The H-bonded (MeOH)(12) cyclododecamer assumes a crown-shaped geometry that has not previously been predicted theoretically or found experimentally.

4,4'-[8b,8c-Bis(ethoxycarbonyl)-4,8-dioxo-2,3,5,6-tetra-hydro-1H,4H-2,3a,4a,6,7a,8a-hexa-azacyclo-penta-[def]fluorene-2,6-diyl]dipyridinium bis-(tetra-fluorido-borate).

In the title compound, C(26)H(32)N(8)O(6) (2+)·2BF(4) (-), the cation is built up from four fused rings, viz. two nearly planar imidazole rings and two triazine rings exhibiting chair conformations. One eth-oxy group is disordered between two positions in an approximate ratio 3:2. The F atoms of the two anions are each rotationally disordered between two orientations in the same 3:2 ratio. The crystal structure is stabilized by inter-molecular N-H⋯O, C-H⋯F and N-H⋯F inter-actions.

N-[(E)-4-Pyridylmethyl-ene]-4-[(E)-4-(4-pyridylmethyl-eneamino)benz-yl]aniline tetra-hydrate.

The title compound, C(25)H(20)N(4)·4H(2)O, crystallizes with the organic mol-ecule lying on a twofold rotation axis through the methyl-ene bridge C atom; there are also two water molecules in the asymmetric unit. The crystal structure is stabilized by C-H⋯O, O-H⋯O and O-H⋯N hydrogen bonds, linking the water mol-ecules to each other and to the pyridine N atom.

N,N'-(Oxydi-p-phenyl-ene)diphthalimide.

The title compound, C(28)H(16)N(2)O(5), is a bis-imide derivative in which two phthalimide units are linked by an oxydi-p-phenyl-ene bridge. The dihedral angle between the planes of the two central benzene rings is 86.1 (4)°. The isoindole groups make dihedral angles of 46.0 (14) and 77.5 (13)° with the attached benzene rings. Inter-molecular C-H⋯O hydrogen bonds contribute to the stability of the structure.

Substituent effects control the self-association of molecular clips in the crystalline state.

We report the X-ray crystal structure of 11 molecular clips and analyze the influence of substituents (e.g., OMe, Me, and NO2) and their location on the observed crystal packing. Molecular clips 3a and 3b form tapelike structures in the crystal due to pi-pi interactions between the aromatic walls. Compounds 3d, 3eC, and 3fC form dimers driven by critical C-H...O interactions and then form tapes driven by pi-pi interactions in the crystal. These two building motifs, pi-pi and C-H...O interactions, can be used to rationalize the enantio- and diastereoselectivity observed in the X-ray crystal structures of the remaining five molecular clips. For example, the C-H...O interactions are found to dictate the formation of homochiral dimers in the structures of (+/-)-3eT and (+/-)-3fT and to control the diastereoselective formation of 6a2-6c2 dimeric motifs with internal p-dimethoxy-o-xylylene walls. Overall, the results suggest that substituent effects that induce even weak intermolecular interactions (e.g., C-H...O) can be used to reliably control crystal packing within glycoluril-based systems.