Opioid Peptides: Potential for Drug Development

Opioid receptors are important targets for the treatment of pain and potentially for other disease states (e.g. mood disorders and drug abuse) as well. Significant recent advances have been made in identifying opioid peptide analogs that exhibit promising in vivo activity for treatment of these maladies. This review focuses on the development and evaluation of opioid peptide analogs demonstrating activity after systemic administration, and recent clinical evaluations of opioid peptides for possible therapeutic use

Synthesis of CJ-15,208, a novel κ-opioid receptor antagonist

The tryptophan isomers of the cyclic tetrapeptide CJ-15,208, reported to be a kappa opioid receptor (KOR) antagonist [Saito, T.; Hirai, H.; Kim, Y. J.; Kojima, Y.; Matsunaga, Y.; Nishida, H.; Sakakibara, T.; Suga, O.; Sujaku, T.; Kojima, N. J. Antibiot. (Tokyo) 2002, 55, 847–854.], were synthesized to determine the tryptophan stereochemistry in the natural product. A strategy was developed to select linear precursor peptides that favor cyclization using molecular modeling, and optimized cyclization conditions are reported. The optical rotation of the l-Trp isomer is consistent with that of the natural product. Unexpectedly both isomers exhibit similar nanomolar affinity for KOR

Mass-to-Light Ratios for M31 Globular Clusters: Age-Dating and a Surprising Metallicity Trend

We have obtained velocity dispersions from Keck high-resolution integrated spectroscopy of ten M31 globular clusters (GCs), including three candidate intermediate-age GCs. We show that these candidates have the same V-band mass-to-light (M/L_V) ratios as the other GCs, implying that they are likely to be old. We also find a trend of derived velocity dispersion with wavelength, but cannot distinguish between a systematic error and a physical effect. Our new measurements are combined with photometric and spectroscopic data from the literature in a reanalysis of all M31 GC M/L_V values. In a combined sample of 27 GCs, we show that the metal-rich GCs have *lower* M/L_V than the metal-poor GCs, in conflict with predictions from stellar population models. Fragmentary data for other galaxies support this observation. The M31 GC fundamental plane is extremely tight, and we follow up an earlier suggestion by Djorgovski to show that the fundamental plane can be used to estimate accurate distances (potentially 10% or better).Comment: 34 pages, accepted to A

Embracing Uncertainty Flexibility: Harnessing a Supervised Tree Kernel to Empower Ensemble Modelling for 2D Echocardiography-Based Prediction of Right Ventricular Volume

The right ventricular (RV) function deterioration strongly predicts clinical outcomes in numerous circumstances. To boost the clinical deployment of ensemble regression methods that quantify RV volumes using tabular data from the widely available two-dimensional echocardiography (2DE), we propose to complement the volume predictions with uncertainty scores. To this end, we employ an instance-based method which uses the learned tree structure to identify the nearest training samples to a target instance and then uses a number of distribution types to more flexibly model the output. The probabilistic and point-prediction performances of the proposed framework are evaluated on a relatively small-scale dataset, comprising 100 end-diastolic and end-systolic RV volumes. The reference values for point performance were obtained from MRI. The results demonstrate that our flexible approach yields improved probabilistic and point performances over other state-of-the-art methods. The appropriateness of the proposed framework is showcased by providing exemplar cases. The estimated uncertainty embodies both aleatoric and epistemic types. This work aligns with trustworthy artificial intelligence since it can be used to enhance the decision-making process and reduce risks. The feature importance scores of our framework can be exploited to reduce the number of required 2DE views which could enhance the proposed pipeline's clinical application.Comment: In the Proceedings of the 16th International Conference of Machine Vision (ICMV 2023), November 15-18, Yerevan, Armeni

The Macrocyclic Peptide Natural Product CJ-15,208 Is Orally Active and Prevents Reinstatement of Extinguished Cocaine-Seeking Behavior

The macrocyclic tetrapeptide natural product CJ-15,208 (cyclo[Phe-d-Pro-Phe-Trp]) exhibited both dose-dependent antinociception and kappa opioid receptor (KOR) antagonist activity after oral administration. CJ-15,208 antagonized a centrally administered KOR selective agonist, providing strong evidence it crosses the blood–brain barrier to reach KOR in the CNS. Orally administered CJ-15,208 also prevented both cocaine- and stress-induced reinstatement of extinguished cocaine-seeking behavior in the conditioned place preference assay in a time- and dose-dependent manner. Thus, CJ-15,208 is a promising lead compound with a unique activity profile for potential development, particularly as a therapeutic to prevent relapse to drug-seeking behavior in abstinent subjects

New Limits on an Intermediate Mass Black Hole in Omega Centauri: II. Dynamical Models

We present a detailed dynamical analysis of the projected density and kinematical data available for the globular cluster Omega Cen. We solve the spherical anisotropic Jeans equation to predict the projected profiles of the RMS velocity in each of the three orthogonal coordinate directions (line of sight, proper motion radial, and proper motion tangential). We fit the models to new HST star count and proper motion data near the cluster center presented in Paper I, combined with existing ground-based measurements. We also derive and model the Gauss-Hermite moments of the observed proper motion distributions. The projected density profile is consistent with being flat near the center, with an upper limit gamma=0.07 on the central logarithmic slope. The RMS proper motion profile is also consistent with being flat near the center, and there are no unusually fast-moving stars. The models provide a good fit and yield a 1-sigma upper limit MBH < 1.2E4 solar masses on the mass of a possible intermediate-mass black hole (IMBH). The inferred upper limit corresponds to MBH/Mtot < 0.43%. We combine this with results for other clusters and discuss the implications for globular cluster IMBH demographics. Tighter limits will be needed to rule out or establish whether globular clusters follow the same black hole demographics correlations as galaxies. The arguments put forward by Noyola et al. (2008) to suspect an IMBH in Omega Cen are not confirmed by our study; the IMBH mass they suggested is firmly ruled out.Comment: 28 pages, 11 figures, ApJ in press. v2 includes additions in response to referee comment

Phenylalanine Stereoisomers of CJ-15,208 and [d-Trp]CJ-15,208 Exhibit Distinctly Different Opioid Activity Profiles

This work is licensed under a Creative Commons Attribution 4.0 International License.The macrocyclic tetrapeptide cyclo[Phe-d-Pro-Phe-Trp] (CJ-15,208) and its stereoisomer cyclo[Phe-d-Pro-Phe-d-Trp] exhibit different opioid activity profiles in vivo. The present study evaluated the influence of the Phe residues’ stereochemistry on the peptides’ opioid activity. Five stereoisomers were synthesized by a combination of solid-phase peptide synthesis and cyclization in solution. The analogs were evaluated in vitro for opioid receptor affinity in radioligand competition binding assays, and for opioid activity and selectivity in vivo in the mouse 55 °C warm-water tail-withdrawal assay. Potential liabilities of locomotor impairment, respiratory depression, acute tolerance development, and place conditioning were also assessed in vivo. All of the stereoisomers exhibited antinociception following either intracerebroventricular or oral administration differentially mediated by multiple opioid receptors, with kappa opioid receptor (KOR) activity contributing for all of the peptides. However, unlike the parent peptides, KOR antagonism was exhibited by only one stereoisomer, while another isomer produced DOR antagonism. The stereoisomers of CJ-15,208 lacked significant respiratory effects, while the [d-Trp]CJ-15,208 stereoisomers did not elicit antinociceptive tolerance. Two isomers, cyclo[d-Phe-d-Pro-d-Phe-Trp] (3) and cyclo[Phe-d-Pro-d-Phe-d-Trp] (5), did not elicit either preference or aversion in a conditioned place preference assay. Collectively, these stereoisomers represent new lead compounds for further investigation in the development of safer opioid analgesics.National Institute on Drug Abuse (R01 DA18832)National Institute on Drug Abuse (R01 DA032928

Direct Phenotypic Screening in Mice: Identification of Individual, Novel Antinociceptive Compounds from a Library of 734 821 Pyrrolidine Bis-piperazines

The hypothesis in the current study is that the simultaneous direct in vivo testing of thousands to millions of systematically arranged mixture-based libraries will facilitate the identification of enhanced individual compounds. Individual compounds identified from such libraries may have increased specificity and decreased side effects early in the discovery phase. Testing began by screening ten diverse scaffolds as single mixtures (ranging from 17 340 to 4 879 681 compounds) for analgesia directly in the mouse tail withdrawal model. The “all X” mixture representing the library TPI-1954 was found to produce significant antinociception and lacked respiratory depression and hyperlocomotor effects using the Comprehensive Laboratory Animal Monitoring System (CLAMS). The TPI-1954 library is a pyrrolidine bis-piperazine and totals 738 192 compounds. This library has 26 functionalities at the first three positions of diversity made up of 28 392 compounds each (26 × 26 × 42) and 42 functionalities at the fourth made up of 19 915 compounds each (26 × 26 × 26). The 120 resulting mixtures representing each of the variable four positions were screened directly in vivo in the mouse 55 °C warm-water tail-withdrawal assay (ip administration). The 120 samples were then ranked in terms of their antinociceptive activity. The synthesis of 54 individual compounds was then carried out. Nine of the individual compounds produced dose-dependent antinociception equivalent to morphine. In practical terms what this means is that one would not expect multiexponential increases in activity as we move from the all-X mixture, to the positional scanning libraries, to the individual compounds. Actually because of the systematic formatting one would typically anticipate steady increases in activity as the complexity of the mixtures is reduced. This is in fact what we see in the current study. One of the final individual compounds identified, TPI 2213-17, lacked significant respiratory depression, locomotor impairment, or sedation. Our results represent an example of this unique approach for screening large mixture-based libraries directly in vivo to rapidly identify individual compounds

Mechanical Systems with Symmetry, Variational Principles, and Integration Algorithms

This paper studies variational principles for mechanical systems with symmetry and their applications to integration algorithms. We recall some general features of how to reduce variational principles in the presence of a symmetry group along with general features of integration algorithms for mechanical systems. Then we describe some integration algorithms based directly on variational principles using a discretization technique of Veselov. The general idea for these variational integrators is to directly discretize Hamilton’s principle rather than the equations of motion in a way that preserves the original systems invariants, notably the symplectic form and, via a discrete version of Noether’s theorem, the momentum map. The resulting mechanical integrators are second-order accurate, implicit, symplectic-momentum algorithms. We apply these integrators to the rigid body and the double spherical pendulum to show that the techniques are competitive with existing integrators

The Relationships Among Compact Stellar Systems: A Fresh View of Ultra Compact Dwarfs

We use a combined imaging and spectroscopic survey of the nearby central cluster galaxy, M87, to assemble a sample of 34 confirmed ultra compact dwarfs (UCDs) with half-light radii of >~ 10 pc measured from Hubble Space Telescope images. This doubles the existing sample in M87, making it the largest such sample for any galaxy, while extending the detection of UCDs to unprecedentedly low luminosities (MV = -9). With this expanded sample, we find no correlation between size and luminosity, in contrast to previous suggestions, and no general correlation between size and galactocentric distance. We explore the relationships between UCDs, less luminous extended clusters (including faint fuzzies), globular clusters (GCs), as well as early-type galaxies and their nuclei, assembling an extensive new catalog of sizes and luminosities for stellar systems. Most of the M87 UCDs follow a tight color-magnitude relation, offset from the metal-poor GCs. This, along with kinematical differences, demonstrates that most UCDs are a distinct population from normal GCs, and not simply a continuation to larger sizes and higher luminosities. The UCD color-magnitude trend couples closely with that for Virgo dwarf elliptical nuclei. We conclude that the M87 UCDs are predominantly stripped nuclei. The brightest and reddest UCDs may be the remnant nuclei of more massive galaxies while a subset of the faintest UCDs may be tidally limited and related to more compact star clusters. In the broader context of galaxy assembly, blue UCDs may trace halo build-up by accretion of low-mass satellites, while red UCDs may be markers of metal-rich bulge formation in larger galaxies.Comment: Re-submitted to the Astronomical Journal after minor revisions. 19 pages, 9 figures, 2 table