Data crowdsourcing on psychomotor and cognitive effects of cannabis via mobile app.

In an effort to educate consumers of cannabis, we created a downloadable application (app) for mobile phones that collects data on the neuropsychological effects related to cannabis use. In particular, the app assessed four domains, these being: (i) psychomotor compensation, (ii) time estimation, (iii) sustained attention, and (iv) response inhibition. These tests were presented as a sequence of video games to be completed in under 10 min. Included in the analysis were 213 users who indicated that they were intoxicated from cannabis at the moment of app use. The control group contained individuals who reported using the app while sober (n = 137). A machine learning model was applied to the data to determine whether a particular pattern of performance was predictive of intoxication, and these results were used to inform the creation of a composite score that reflected aggregate performance for all four (i-iv) video games. Relative to the control group, the largest performance decrements were discovered within the initial 120 min after self-administration. These deficits abated as the time-since-use lengthened, and this pattern was consistent with the time-course of subjectively reported intoxication. Although significant limitations in interpretation exist due to the naturalistic and self-report data collection method, this proof-of-concept study points toward the potential utility of mobile app detection of cannabis effect. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Alzheimer's Disease and Related Disorders Prevalence Differs by Appalachian Residence in Ohio.

BACKGROUND: Areas within the Appalachian region may have a greater burden of under diagnosed Alzheimer's disease and related disorders (ADRD). OBJECTIVE: To estimate the prevalence of ADRD in the Appalachian counties of Ohio, and to determine if differences exist by geographic location (Appalachian/non-Appalachian and rural/urban) and across time among Medicare beneficiaries. METHODS: Centers for Medicare and Medicaid Services Public Use Files from 2007-2017 were used to estimate county-level ADRD prevalence among all fee-for-service beneficiaries in Ohio. Negative binomial regression was used to estimate prevalence overall, by Appalachian Regional Commission's Appalachian/non-Appalachian designation, and by rural/urban (Rural-Urban Continuum Codes) classification. Models were repeated, adjusting for county-level demographics and comorbidities. RESULTS: The prevalence of ADRD varied by both Appalachian residence and rural status (p = 0.008). Before adjustment by county-level demographics and comorbidities, the prevalence of ADRD in urban Appalachian counties was 1-3% lower than in urban non-Appalachian counties, while rural Appalachian counties had 2-3% higher prevalence compared to rural non-Appalachian counties. After adjustment, the differences between prevalence ratios were accentuated; the prevalence ratio was consistently higher for rural Appalachian counties, yet varied across the study period for urban counties (1.03 in 2007 to 0.97 in 2017). CONCLUSION: The results suggest a disparate burden of ADRD in Ohio with higher prevalence in rural Appalachian counties. This potential difference by Appalachian region is important to consider for availability of services and subsequent delivery of care. In order to better understand the disparity, further epidemiologic studies are necessary to better estimate the burden of ADRD.

Target identification for a Hedgehog pathway inhibitor reveals the receptor GPR39.

Hedgehog (Hh) signaling determines cell fate during development and can drive tumorigenesis. We performed a screen for new compounds that can impinge on Hh signaling downstream of Smoothened (Smo). A series of cyclohexyl-methyl aminopyrimidine chemotype compounds ('CMAPs') were identified that could block pathway signaling in a Smo-independent manner. In addition to inhibiting Hh signaling, the compounds generated inositol phosphates through an unknown GPCR. Correlation of GPCR mRNA expression levels with compound activity across cell lines suggested the target to be the orphan receptor GPR39. RNA interference or cDNA overexpression of GPR39 demonstrated that the receptor is necessary for compound activity. We propose a model in which CMAPs activate GPR39, which signals to the Gli transcription factors and blocks signaling. In addition to the discovery of GPR39 as a new target that impinges on Hh signaling, we report on small-molecule modulators of the receptor that will enable in vitro interrogation of GPR39 signaling in different cellular contexts.

Small molecule antagonists in distinct binding modes inhibit drug-resistant mutant of smoothened.

Several small molecule antagonists for Smoothened (Smo) have been developed, and achieved promising preclinical efficacy in cancers that are dependent on Hedgehog (Hh) signaling. However, in a recent clinical study, a drug-resistant D473H SMO mutant was identified that is thought to be responsible for cancer relapse in a patient with medulloblastoma. Here, we report two Smo antagonists that bind to distinct sites, as compared to known antagonists and agonists, and inhibit both wild-type and mutant Smo. These findings provide an insight of the ligand-binding sites of Smo and a basis for the development of potential therapeutics for tumors with drug-resistant Smo mutations.

1-amino-4-benzylphthalazines as orally bioavailable smoothened antagonists with antitumor activity.

Abnormal activation of the Hedgehog (Hh) signaling pathway has been linked to several types of human cancers, and the development of small-molecule inhibitors of this pathway represents a promising route toward novel anticancer therapeutics. A cell-based screen performed in our laboratories identified a new class of Hh pathway inhibitors, 1-amino-4-benzylphthalazines, that act via antagonism of the Smoothened receptor. A variety of analogues were synthesized and their structure-activity relationships determined. This optimization resulted in the discovery of high affinity Smoothened antagonists, one of which was further profiled in vivo. This compound displayed a good pharmacokinetic profile and also afforded tumor regression in a genetic mouse model of medulloblastoma.

Identification and structure-activity relationships of ortho-biphenyl carboxamides as potent Smoothened antagonists inhibiting the Hedgehog signaling pathway.

Ortho-biphenyl carboxamides, originally prepared as inhibitors of microsomal triglyceride transfer protein (MTP) have been identified as novel inhibitors of the Hedgehog signaling pathway. Structure-activity relationship studies for this class of compounds reduced MTP inhibitory activity and led to low nanomolar Hedgehog inhibitors. Binding assays revealed that the compounds act as antagonists of Smoothened and show cross-reactivity for both the human and mouse receptor.

Chemical genetic transcriptional fingerprinting for selectivity profiling of kinase inhibitors.

The importance of protein kinases as a major class of drug targets across multiple diseases has generated a critical need for technologies that enable the identification of potent and selective kinase inhibitors. Bruton's tyrosine kinase (Btk) is a compelling drug target in multiple therapeutic areas, including systemic lupus erythematosus, asthma, rheumatoid arthritis, and B cell malignancies. We have combined potent, selective kinase inhibition through chemical genetics with gene expression profiling to identify a "fingerprint" of transcriptional changes associated with selective Btk kinase inhibition. The Btk transcriptional fingerprint shows remarkable relevance for Btk's biological roles and was used for functional selectivity profiling of two kinase inhibitor compounds. The fingerprint was able to rank the compounds by relative selectivity for Btk, and revealed broader off-target effects than observed in a broad panel of biochemical kinase cross screens. In addition to being useful for functional selectivity profiling, the fingerprint genes are themselves potential preclinical and clinical biomarkers for developing Btk-directed therapies.

Synthesis of covalent probes for the radiolabeling of the cannabinoid receptor.

The main psychoactive constituent of marijuana, (-)-Delta(9)-tetrahydrocannabinol, produces most of its physiological effects by interacting with the CB1 cannabinoid receptor, a membrane protein belonging to the large superfamily of G-protein coupled receptors. The 3-D structure of the receptor binding site is of value in the design of novel medications for a variety of therapeutic indications. To obtain information on the amino acid residues associated with this binding site, we have designed and synthesized a cannabinergic CB1 ligand prototype carrying an electrophilic isothiocyanato group capable of reacting covalently with amino acid residues bearing thiol or unprotonated amino groups. The ligand also incorporates an iodide atom, which can serve as a high-activity radiolabel. The key step in our synthesis involves a rapid intramolecular Diels-Alder reaction of a transiently formed o-quinone methide, which proceeds stereospecifically with the formation of the tricyclic cannabinoid template. Introduction of the iodo group is the last step in the sequence and is compatible with the use of (125)I-radiolabel.