Larval performance, osteological development and skeletal abnormalities in wreckfish (Polyprion americanus) under a standard rearing protocol and different light intensities and rearing temperatures

Wreckfish (Polyprion americanus) is a promising new species for aquaculture diversification due to its fast growth, late reproductive maturation, and high market price. Nowadays, low larval survival is considered the biggest limitation in wreckfish farming. Here, the fertilization, hatching, and survival rates of 20 spawning events from an established wreckfish broodstock have been analyzed in order to characterize the main bottlenecks in wreckfish early and larval development. The ontogenesis of the skeletal system and the incidence of skeletal deformities have been assessed in 632 samples from larval rearing trials using an acid free double staining protocol. Furthermore, the effect of different rearing temperatures (13 vs 16 ºC) and light intensities at water surface (600, 900 and 1200 lux) on the skeletal development have been also explored. Results showed as while a variable egg fertilization rate (61.75 ± 34.62%) were achieved, a very poor hatching (4.52 ± 9.27%) and survival rate (0.01 ± 0.00%) until 71 days post hatching (dph) were observed. Swimbladder inflation was first seen at 7 dph, and at 11 and 25 dph a 61-63% of fish functional swimbladder. The first skeletal structures to be formed were those related with breathing and feeding activities (e.g., cleithrum, Meckel¿s cartilage and ceratobranchials) and were visible in larvae of 4-5 mm of standard length (SL). Ossification of the vertebral column progressed in an anterior-to-posterior direction, being fully ossified at 7-14 mm of SL. Regarding the skeletal deformities, a high incidence (63%) of jaw deformity (particularly lower jaw deformity) was observed in larvae of 4-5 of SL, progressively decreasing (up to 5%) in larvae of >6 mm of SL. Deformed vertebrae (compressed, fused, and/or displaced) were mainly located at the 13 to 15th vertebra, and were associated to lordosis, most probably due to the no swimbladder inflation. No clear relationship between temperature and the incidence of lower jaw deformity was observed during endotrophic larval development. Light intensity had a clear effect on survival but not in skeletal development. Larvae reared under 600 lux had lower survival (0.15 ± 0.21%) at 21 dph than when reared with 900 and 1200 lux (0.6 ± 0.28 and 0.7 ± 0.28%, respectively). The present research work represents an important step forward to solve wreckfish larval rearing bottlenecks, suggesting that while temperature and light intensity might have an effect on wreckfish larval survival and development, egg quality and incubation seemed to be the most limiting factors for successful wreckfish aquaculture.This work was partially funded by the NEWSPEC project Unión Europea a través del Fondo Europeo Marítimo y de Pesca (FEMP). M.C., P.N., and I.F. thanks the support from the network LARVAplus “Estrategias de desarrollo y mejora de la producción de larvas de peces en Iberoamerica” (117RT0521) funded by the Programa Iberoamericano de Ciencia y Tecnologia para el Desarrollo (CYTED)

Potent and Subtype-Selective Dopamine D2 Receptor Biased Partial Agonists Discovered via an Ugi-Based Approach

Using a previously unexplored, efficient, and versatile multicomponent method, we herein report the rapid generation of novel potent and subtype-selective DRD2 biased partial agonists. This strategy exemplifies the search for diverse and previously unexplored moieties for the secondary/allosteric pharmacophore of the common phenyl-piperazine scaffold. The pharmacological characterization of the new compound series led to the identification of several ligands with excellent DRD2 affinity and subtype selectivity and remarkable functional selectivity for either the cAMP (22a and 24d) or the β-arrestin (27a and 29c) signaling pathways. These results were further interpreted on the basis of molecular models of these ligands in complex with the recent DRD2 crystal structures, highlighting the critical role of the secondary/allosteric pharmacophore in modulating the functional selectivity profileThis work was financially supported by the Consellería de Cultura, Educación e Ordenación Universitaria of the Galician Government: (grant: ED431B 2020/43), Centro Singular de Investigación de Galicia accreditation 2019-2022 (ED431G 2019/03), the Spanish Ministerio de Economía y Competitividad (SAF2017-84117-R), the European Regional Development Fund (ERDF) and the Swedish Research Council. Additional support from the Swedish strategic research program eSSENCE and Deputación da Coruña (grant: 2019000011466) are acknowledged. The computations were performed on resources provided by the Swedish National Infrastructure for Computing (SNIC). This research program was developed within the framework of the European COST action ERNEST (CA 18133)S

Potent and subtype-selective dopamine D2 receptor biased partial agonists discovered via an Ugi-based approach

Using a previously unexplored, efficient, and versatile multicomponent method, we herein report the rapid generation of novel potent and subtype-selective DRD2 biased partial agonists. This strategy exemplifies the search for diverse and previously unexplored moieties for the secondary/allosteric pharmacophore of the common phenyl-piperazine scaffold. The pharmacological characterization of the new compound series led to the identification of several ligands with excellent DRD2 affinity and subtype selectivity and remarkable functional selectivity for either the cAMP (22a and 24d) or the β-arrestin (27a and 29c) signaling pathways. These results were further interpreted on the basis of molecular models of these ligands in complex with the recent DRD2 crystal structures, highlighting the critical role of the secondary/allosteric pharmacophore in modulating the functional selectivity profileThis work was financially supported by the Consellería de Cultura, Educación e Ordenación Universitaria of the Galician Government: (grant: ED431B 2020/43), Centro Singular de Investigación de Galicia accreditation 2019-2022 (ED431G 2019/03), the Spanish Ministerio de Economía y Competitividad (SAF2017-84117-R), the European Regional Development Fund (ERDF) and the Swedish Research Council. Additional support from the Swedish strategic research program eSSENCE and Deputación da Coruña (grant: 2019000011466) are acknowledged. The computations were performed on resources provided by the Swedish National Infrastructure for Computing (SNIC). This research program was developed within the framework of the European COST action ERNEST (CA 18133)S

Exploring Non-orthosteric Interactions with a Series of Potent and Selective A(3) Antagonists

: A library of potent and highly A3AR selective pyrimidinebased compounds was designed to explore non-orthosteric interactions within this receptor. Starting from a prototypical orthosteric A3AR antagonist (ISVY130), the structure-based design explored functionalized residues at the exocyclic amide L1 region and aimed to provide additional interactions outside the A3AR orthosteric site. The novel ligands were assembled through an efficient and succinct synthetic approach, resulting in compounds that retain the A3AR potent and selective profile while improving the solubility of the original scaffold. The experimentally demonstrated tolerability of the L1 region to structural functionalization was further assessed by molecular dynamics simulations, giving hints of the non-orthosteric interactions explored by these series. The results pave the way to explore newly functionalized A3AR ligands, including covalent drugs and molecular probes for diagnostic and delivery purposes