We recently reported on a controlled deactivation/detoxification approach for obtaining cannabinoids with improved druggability. Our design incorporates a metabolically labile ester group at strategic positions within the THC structure. We have now synthesized a series of (-)-Δ(8)-THC analogues encompassing a carboxyester group within the 3-alkyl chain in an effort to explore this novel cannabinergic chemotype for CB receptor binding affinity, in vitro and in vivo potency and efficacy, as well as controlled deactivation by plasma esterases. We have also probed the chain's polar characteristics with regard to fast onset and short duration of action. Our lead molecule, namely 2-[(6aR,10aR)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-3-yl]-2-methyl-propanoic acid 3-cyano-propyl ester (AM7438), showed picomolar affinity for CB receptors and is deactivated by plasma esterases while the respective acid metabolite is inactive. In further in vitro and in vivo experiments, the compound was found to be a remarkably potent and efficacious CB1 receptor agonist with relatively fast onset/offset of action.

Propanoic acid

Lipophilicity

Druggability

10.1021/jm501165d

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Citations (27)

Cannabinoid-induced lower lip retraction in rats

Psychopharmacology (2018)

Girish R. Chopda Spyros P. Nikas Rishi Sharma Shashank Kulkarni Alexandros Makriyannis

Rimonabant

Cannabinoid Receptor Agonists

Cannabinoid receptor antagonist

Inverse agonist

10.1007/s00213-018-5125-z

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Citations (3)

Identification of annotated bioactive molecules that impair motility of the blood fluke Schistosoma mansoni

International Journal for Parasitology Drugs and Drug Resistance (2020)

Thomas Duguet Anastasia Glebov Asimah Hussain Shashank Kulkarni Igor Mochalkin

Neglected tropical diseases are of growing worldwide concern and schistosomiasis, caused by parasitic flatworms, continues to be a major threat with more than 200 million people requiring preventive treatment. As praziquantel (PZQ) remains the treatment of choice, an urgent need for alternative treatments motivates research to identify new lead compounds that would complement PZQ by filling the therapeutic gaps associated with this treatment. Because impairing parasite neurotransmission remains a core strategy for control of parasitic helminths, we screened a library of 708 compounds with validated biological activity in humans on the blood fluke Schistosoma mansoni, measuring their effect on the motility on schistosomulae and adult worms. The primary phenotypic screen performed on schistosomulae identified 70 compounds that induced changes in viability and/or motility. Screening different concentrations and incubation times identified molecules with fast onset of activity on both life stages at low concentration (1 μM). To complement this study, similar assays were performed with chemical analogs of the cholinomimetic drug arecoline and the calcilytic molecule NPS-2143, two compounds that rapidly inhibited schistosome motility; 17 arecoline and 302 NPS-2143 analogs were tested to enlarge the pool of schistosomicidal molecules. Finally, validated hit compounds were tested on three functionally-validated neuroregulatory S. mansoni G-protein coupled receptors (GPCRs): Sm5HTR (serotonin-sensitive), SmGPR2 (histamine) and SmD2 (dopamine), revealing NPS-2143 and analogs as potent inhibitors of dopamine/epinine responses on both human and S. mansoni GPCRs. This study highlights the potential for repurposing known human therapeutic agents for potential schistosomicidal effects and expands the list of hits for further progression.

Schistosoma

10.1016/j.ijpddr.2020.05.002

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Citations (14)

Metastatic appendiceal adenocarcinoma presenting late as epididymo-orchitis: a case report and review of literature

BMC Urology (2004)

Shashank Kulkarni A. J. Coup John B. C. Kershaw Noor Buchholz

Whereas testicular metastases are in themselves a rare entity, testicular secondaries from an appendiceal carcinoma have not yet been described. The case also illustrates the diagnostic dilemma of a tumour presenting as epididymo-orchitis. The authors present a case of an appendiceal carcinoma that, two years after radical therapy, manifested as a secondary in the testis. It was misdiagnosed as an epididymo-orchitis and was only revealed through histology. Practitioners need to remember that long-standing testicular inflammation may result form secondary tumours. Even "exotic" primary tumours in the medical history of the patient must give rise to an increased suspicion threshold.

Orchitis

10.1186/1471-2490-4-1

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Citations (29)

Modulation of Host–Parasite Interactions with Small Molecules TargetingSchistosoma mansonimicroRNAs

ACS Infectious Diseases (2022)

Youssef Hamway Kaspar Zimmermann Marcel J. J. Blommers Mariana V. Sousa Cécile Häberli

Parasites use different strategies of communication with their hosts. One communication channel that has been studied in recent years is the use of vesicle microRNAs to influence the host immune system by trematodes. sma-microRNA-10, secreted from Schistosoma mansoni, has been shown to influence the fate of host T-cells through manipulation of the NF-κB pathway. We have identified low molecular weight tool compounds that can interfere with this microRNA-mediated manipulation of the host immune system. We used a fragment-based screening approach by means of nuclear magnetic resonance (NMR) to identify binders to the precursor of the parasite sma-microRNA-10 present in their extracellular vesicles. The small fragments identified were used to select larger molecules. These molecules were shown to counteract the inhibition of NF-κB activity by sma-microRNA-10 in cell-based assays.

10.1021/acsinfecdis.2c00360

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Citations (1)

Purchasing

Journal of Business Strategy (1996)

Shashank Kulkarni

Your purchasing department spends 50% to 70% of every company revenue dollar on items from raw materials to services. All the “just‐in‐time,” electronic data interchanges, reengineering, rightsizing, and team development your company pursues will not have as much real bottom‐line impact as a radical change in the way purchasing managers do their jobs.

Liberian dollar

Purchasing process

Business process reengineering

10.1108/eb039803

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Citations (0)