Development of pyrimidone D1 dopamine receptor positive allosteric modulators

MLS1082 is a structurally novel pyrimidone-based D1-like dopamine receptor positive allosteric modulator. Potentiation of D1 dopamine receptor (D1R) signaling is a therapeutic strategy for treating neurocognitive disorders. Here, we investigate the relationship between D1R potentiation and two prominent structural features of MLS1082, namely the pendant N-aryl and C-alkyl groups on the pyrimidone ring. To this end, we synthesized 24 new analogues and characterized their ability to potentiate dopamine signaling at the D1R and the closely related D5R. We identified structure–activity relationship trends for both aryl and alkyl modifications and our efforts afforded several analogues with improvements in activity. The most effective analogues demonstrated an approximately 8-fold amplification of dopamine-mediated D1R signaling. These findings advance the understanding of structural moieties underlying the activity of pyrimidone-based D1R positive allosteric modulators

Structure-activity investigation of a G protein-biased agonist reveals molecular determinants for biased signaling of the D2 dopamine receptor

The dopamine D2 receptor (D2R) is known to elicit effects through activating two major signaling pathways mediated by either G proteins (Gi/o) or β-arrestins. However, the specific role of each pathway in physiological or therapeutic activities is not known with certainty. One approach to the dissection of these pathways is through the use of drugs that can selectively modulate one pathway vs. the other through a mechanism known as functional selectivity or biased signaling. Our laboratory has previously described a G protein signaling-biased agonist, MLS1547, for the D2R using a variety of in vitro functional assays. To further evaluate the biased signaling activity of this compound, we investigated its ability to promote D2R internalization, a process known to be mediated by β-arrestin. Using multiple cellular systems and techniques, we found that MLS1547 promotes little D2R internalization, which is consistent with its inability to recruit β-arrestin. Importantly, we validated these results in primary striatal neurons where the D2R is most highly expressed suggesting that MLS1547 will exhibit biased signaling activity in vivo. In an effort to optimize and further explore structure-activity relationships (SAR) for this scaffold, we conducted an iterative chemistry campaign to synthesize and characterize novel analogs of MLS1547. The resulting analysis confirmed previously described SAR requirements for G protein-biased agonist activity and, importantly, elucidated new structural features that are critical for agonist efficacy and signaling bias of the MLS1547 scaffold. One of the most important determinants for G protein-biased signaling is the interaction of a hydrophobic moiety of the compound with a defined pocket formed by residues within transmembrane five and extracellular loop two of the D2R. These results shed new light on the mechanism of biased signaling of the D2R and may lead to improved functionally-selective molecules

Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist

To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders

Snipe taxonomy based on vocal and non-vocal sound displays: the South American Snipe is two species

We analysed breeding sounds of the two subspecies of South American Snipe Gallinago paraguaiae paraguaiae and Gallinago paraguaiae magellanica to determine whether they might be different species: loud vocalizations given on the ground, and the tail‐generated Winnow given in aerial display. Sounds of the two taxa differ qualitatively and quantitatively. Both taxa utter two types of ground call. In G. p. paraguaiae, the calls are bouts of identical sound elements repeated rhythmically and slowly (about five elements per second (Hz)) or rapidly (about 11 Hz). One call of G. p. magellanica is qualitatively similar to those of G. p. paraguaiae but sound elements are repeated more slowly (about 3 Hz). However, its other call type differs strikingly: it is a bout of rhythmically repeated sound couplets, each containing two kinds of sound element. The Winnow of G. p. paraguaiae is a series of sound elements that gradually increase in duration and energy; by contrast, that of G. p. magellanica has two or more kinds of sound element that roughly alternate and are repeated as sets, imparting a stuttering quality. Sounds of the related Puna Snipe (Gallinago andina) resemble but differ quantitatively from those of G. p. paraguaiae. Differences in breeding sounds of G. p. paraguaiae and G. p. magellanica are strong and hold throughout their geographical range. Therefore we suggest that the two taxa be considered different species: G. paraguaiae east of the Andes in much of South America except Patagonia, and G. magellanica in central and southern Chile, Argentina east of the Andes across Patagonia, and Falklands/Malvinas.Fil: Miller, Edward H.. Memorial University Of Newfoundland; CanadáFil: Areta, Juan Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Bio y Geociencias del NOA. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Museo de Ciencias Naturales. Instituto de Bio y Geociencias del NOA; ArgentinaFil: Jaramillo, Alvaro. San Francisco Bay Bird Observatory; Estados UnidosFil: Imberti, Santiago. Asociación Ambiente Sur, Rio Gallegos; ArgentinaFil: Matus, Ricardo. Kilómetro 7 Sur; Chil

Sea-level rise and refuge habitats for tidal marsh species: Can artificial islands save the California Ridgway's rail?

Terrestrial species living in intertidal habitats experience refuge limitation during periods of tidal inundation, which may be exacerbated by seasonal variation in vegetation structure, tidal cycles, and land-use change. Sea-level rise projections indicate the severity of refuge limitation may increase. Artificial habitats that provide escape cover during tidal inundation have been proposed as a temporary solution to alleviate these limitations. We tested for evidence of refuge habitat limitation in a population of endangered California Ridgway's rail (Rallus obsoletus obsoletus; hereafter California rail) through use of artificial floating island habitats provided during two winters. Previous studies demonstrated that California rail mortality was especially high during the winter and periods of increased tidal inundation, suggesting that tidal refuge habitat is critical to survival. In our study, California rail regularly used artificial islands during higher tides and daylight hours. When tide levels inundated the marsh plain, use of artificial islands was at least 300 times more frequent than would be expected if California rails used artificial habitats proportional to their availability (0.016%). Probability of use varied among islands, and low levels of use were observed at night. These patterns may result from anti-predator behaviors and heterogeneity in either rail density or availability of natural refuges. Endemic saltmarsh species are increasingly at risk from habitat change resulting from sea-level rise and development of adjacent uplands. Escape cover during tidal inundation may need to be supplemented if species are to survive. Artificial habitats may provide effective short-term mitigation for habitat change and sea-level rise in tidal marsh environments, particularly for conservation-reliant species such as California rails

The design of p-i-n-bipolar transimpedance pre-amplifiers for optical receivers

The factors limiting speed, sensitivity and dynamic range in p-i-n-b.j.t. transimpedance pre-amplifiers for optical receivers are examined. It is shown that a common-collector front end design is the best input configuration if a wideband response with good sensitivity is required. Two low-cost discrete pre-amplifier designs suitable for 140 Mbit/s and 650 Mbit/s are presented, together with three monolithic integrated circuits. The i.c.s were used in 320 Mbit/s receivers and had typical sensitivities of ¿34.6 dBm and optical dynamic ranges of at least 18.4 dB. The effect of circuit parasitics and of reducing transistor geometry on the i.e. performance is examined