Realisation of small molecule libraries based on frameworks distantly related to natural products.

The availability of high-quality screening compounds is of paramount importance for the discovery of innovative new medicines. Natural product (NP) frameworks can inspire the design of productive compound libraries. Here, we describe the design and synthesis of four compound libraries based on scaffolds that have broad NP-like features, but that are only distantly related to specific NPs. The optimisation of syntheses of the scaffolds using [5 + 2] cycloaddition chemistry is detailed, together with methods to yield exemplar decorated screening compounds. In each case, a library was nominated for production, leading to a total of >2900 screening compounds that augmented the Joint European Compound Library of the European Lead Factory.

Genome Sequences of Cluster K Mycobacteriophages DrHayes, Urkel, and SamuelLPlaqson.

Mycobacteriophages DrHayes, Urkel, and SamuelLPlaqson were isolated from soil samples in Spokane, WA, using Mycobacterium smegmatis mc2155 grown at room temperature. The three genomes differ by only a few nucleotides, are 60,526 bp long, have 97 predicted protein-coding genes and one tRNA gene, and are members of subcluster K1.

Amphetamine lowers brain stimulation reward (BSR) threshold in alcohol-preferring (P) and -nonpreferring (NP) rats: regulation by D-sub-1 and D-sub-2 receptors in the nucleus accumbens.

Differences in the mesolimbic dopamine (DA) pathway that regulates alcohol preference may also increase sensitivity to the reinforcing effects of other drugs of abuse. In the present study, the curve-shift (rate-frequency) paradigm was used to quantify the interaction of amphetamine with the rewarding effects of lateral hypothalamic brain stimulation reward (BSR) in alcohol-preferring (P) and -nonpreferring (NP) rats. The role of D-sub-1 and D-sub-2 DA receptors of the nucleus accumbens (NAcc) in mediating the reward-potentiating effects of amphetamine was also determined. Animals were tested with randomly administered amphetamine (0.25, 0.75, 1.25 mg/kg ip), DA-receptor antagonists (SCH 23390 [2.0 microg, 5.0 microg]; eticlopride [2.0 microg, 5.0 microg]), or a combination of the 2 (SCH 23390 [2.0 microg, 5.0 microg] + 0.75 mg/kg amphetamine; eticlopride [2.0 microg, 5.0 microg] + 0.75 mg/kg amphetamine). Amphetamine produced comparable dose-related leftward shifts in the rate-frequency function for both P and NP rats, with a greater than 60% reduction observed in BSR threshold. On intervening days, baseline threshold was unaltered between tests and similar between rat lines. Unilateral infusion in the NAcc of either the D-sub-1 or D-sub-2 receptor antagonist produced rightward shifts in the rate-frequency function of amphetamine, completely reversing-attenuating its reward-enhancing effects. The results demonstrate that amphetamine produces similar threshold-lowering effects in both P and NP rats and that the reward-potentiating effects of amphetamine do not correlate with alcohol preference under the conditions of the present study.

Brain stimulation reward performance and sucrose maintained behaviors in alcohol-preferring and -nonpreferring rats.

BACKGROUND: The relation between ethanol (EtOH) preference and sensitivity to brain stimulation reward (BSR) was examined under multiples schedules of reinforcement in the current study. For comparison, the study also examined the relation between EtOH preference and motivation for a sweet, palatable sucrose solution under similar schedules of reinforcement. METHODS: To investigate sensitivity to BSR performance, alcohol-preferring and -nonpreferring rats were tested using the curve-shift (rate-frequency) paradigm under several intensity levels during a 20-min session. Animals were first trained under an optimal current intensity, which produced maximal responding (i.e., 100%) across a series of descending frequencies (i.e., 300-20 Hz). BSR was then evaluated at 100%, 75%, and 50% of the optimal current. The sensitivity of the curve-shift method was further evaluated under the animal's optimal current using the FR1, FR6, and FR12 schedules. To examine responding for the sucrose solution, a separate group of alcohol-preferring and -nonpreferring rats was initially stabilized on an FR1 schedule and then subsequently on FR6 and FR12 schedules. RESULTS: The results demonstrated that reducing the reinforcing efficacy of BSR via reduction in current intensity/reinforcement schedule produced marked orderly rightward shifts in the rate-frequency curves relating responding to stimulation frequency in both rat lines. However, no differences were found between the lines with either manipulation. Specifically, both lines demonstrated orderly reductions in response rate and increases in BSR threshold parameters (i.e., half maximal frequency/responding, minimum and maximum frequencies). In contrast to BSR, genetic selection for EtOH preference was highly associated with responding for the sweet, palatable sucrose solution. The association was even more salient as the reinforcement schedule increased (i.e., reward cost). CONCLUSION: The results demonstrate that responding for BSR is not associated with EtOH preference, insofar as alcohol-preferring and -nonpreferring rats respond similarly under an array of reinforcement schedules and current intensities. In contrast, genetic selection for EtOH preference is highly associated with responding for a palatable sucrose reward, and the relation increases as the reward cost for the sucrose increases. These findings suggest that similar/overlapping mechanisms of action regulate the reinforcing properties of EtOH and sucrose but that overlapping yet distinct neuronal mechanism may modulate the reward characteristics of BSR and EtOH preference.

Differential responding for brain stimulation reward and sucrose in high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rats.

BACKGROUND: This study examined the associations among selective breeding for alcohol preference, intake of sweet solutions, and responding for brain stimulation reward (BSR), a nonoral reinforcer, in alcohol-preferring high-alcohol-drinking (HAD)-1 and nonpreferring low-alcohol-drinking (LAD)-1 rats. METHODS: Adult male HAD-1 and LAD-1 rats were trained to lever press for medial forebrain bundle stimulation. Current intensity was varied in separate sessions to generate a rate/intensity function. To further examine BSR responding, the animals responded for stimulation at 100 Hz and at a fixed current intensity on an FR1 schedule. In subsequent sessions, the schedule was increased to FR6 and then to FR12. To examine responding for the sucrose solution, we trained a separate group of HAD-1/LAD-1 rats to bar press for sucrose on an FR1 schedule. Similar to the BSR experiment, in following sessions, the schedule was increased to an FR6 and then to an FR12 schedule. RESULTS: No significant differences were observed between the two rat lines across a range of current intensities. As the reinforcement schedule increased, HAD-1 rats exhibited a dramatic decrease in BSR responding, whereas the LAD-1 rats displayed a more protracted reduction. In contrast to BSR, marked elevations in responding were observed for sucrose as the schedule increased. However, in HAD-1 rats, response rates were similar on the FR6 and FR12 schedules, whereas LAD-1 rats showed a reduction in response rates from the FR6 to FR12 schedule. Furthermore, HAD-1 rats exhibited significantly more responses compared with LAD-1 rats across the three reinforcement schedules. An analysis of the response profile for the three reinforcement schedules suggested that few if any postreinforcement pauses were exhibited when the reinforcer was BSR compared with sucrose in both lines. CONCLUSION: Medial forebrain bundle BSR is a powerful reinforcer in both HAD-1 and LAD-1 lines. However, BSR responding was not associated with selective breeding for alcohol preference. In contrast, selective breeding for alcohol preference was associated with sucrose consumption, especially as the amount of work increased. The lack of correspondence between BSR and sweet taste rewards in HAD-1 and LAD-1 lines may suggest important differences yet an overlapping brain reward mechanism in the control of motivated behaviors in these selected lines.