Nadine Jagerovic

CB1 cannabinoid antagonists: Structure-activity relationships and potential therapeutic applications

During the last decade there has been a growing interest towards the modulation of the cannabinoid CB1 receptor. The identification of CB1 cannabinoid receptor antagonists has been one of the major advances in cannabinoid research. Thus, the development of these ligands has opened new therapeutic applications. Since the discovery of the first cannabinoid receptor antagonist, rimonabant, by Sanofi in 1994, a large number of structural variations within this chemical series of 1,5-diarylpyrazoles have been described. So far, all attempts to identify novel structures for CB1 antagonists have been based on one or more pharmacophoric elements of the rimonabant structure. The advanced clinical trials of rimonabant confirm the therapeutic potential value of CB1 antagonists for the treatment of obesity. In addition, the results of pharmacological and clinical studies reveal other effective pharmacotherapeutic applications. The current review will mainly focus on the structure-activity relationships that have been established for antagonists/inverse agonists that bind to the CB1 cannabinoid receptors and on their therapeutic applications.

Photosensitization with derivatives of chlorin p6

Biophysical and photobiological properties of three derivatives of chlorin p6 were examined. These agents can be considered as lysyl analogs of the aspartyl chlorin NPe6. Lysyl chlorin p6 diester (LCP) and the triester analog (LCP2) were readily accumulated by murine leukemia L1210 cells, localized in lysosomes, and were relatively inefficient photosensitizing agents in vitro. In contrast, lysyl chlorin e6 imide (LCI) was poorly accumulated, concentrated in mitochondrial and plasma membranes, but was more efficacious. LCI was the most effective agent with regard to photosensitization of a murine tumor in vivo, but all three agents caused substantially more toxicity than was observed with NPe6.

Syntheses and preliminary in vivo photodynamic efficacy of benzoporphyrin derivatives from phylloerythrin and rhodoporphyrin XV methyl esters and aspartyl amides

Abstract Efficient approaches to the synthesis of methyl esters and aspartyl amides of so-called ring ‘A’-benzoporphyrin derivatives from rhodoporphyrin XV dimethyl ester 10 and 3-vinylphylloerythrin methyl ester 22 are reported. The benzo-rings in the products are obtained by way of Diels-Alder [4+2] cyclizations which employ a dieneophile and the vinyl and 2,3-double bonds in the starting materials as the diene. In the 3-vinyl-phylloerythrin series, the presence of the 131-keto-group in ring E inhibits the Diels-Alder reaction with dimethyl acetylenedicarboxylate, but with more reactive dienophiles, such as tetracyanoethylene, the Diels-Alder adduct was isolated in modest yield. Protection of the 131-keto- group as a ketal or thioketal afforded the intermediate benzoporphyrin adducts, which were rearranged to trans- and cis- isomers on reacting with triethylamine and 1,8-diazabiclo[5,4,0]undec-7-ene, respectively. Among the sensitizers tested so far, the benzoporphyrin derivative (cis- isomer) obtained from rhodoporphyrin XV di-tert- butyl aspartate showed the best in vivo photosensitizing activity in DBA/2 mice transplanted with SMT/F tumors.

Selective, nontoxic CB2 cannabinoid o-quinone with in vivo activity against triple-negative breast cancer

Triple-negative breast cancer (TNBC) represents a subtype of breast cancer characterized by high aggressiveness. There is no current targeted therapy for these patients whose prognosis, as a group, is very poor. Here, we report the synthesis and evaluation of a potent antitumor agent in vivo for this type of breast cancer designed as a combination of quinone/cannabinoid pharmacophores. This new compound (10) has been selected from a series of chromenopyrazolediones with full selectivity for the nonpsychotropic CB2 cannabinoid receptor and with efficacy in inducing death of human TNBC cell lines. The dual concept quinone/cannabinoid was supported by the fact that compound 10 exerts antitumor effect by inducing cell apoptosis through activation of CB2 receptors and through oxidative stress. Notably, it did not show either cytotoxicity on noncancerous human mammary epithelial cells nor toxic effects in vivo, suggesting that it may be a new therapeutic tool for the management of TNBC.

Antiprotozoal activity of 1-phenethyl-4-aminopiperidine derivatives

ABSTRACT A series of 44 4-aminopiperidine derivatives was screened in vitro against four protozoan parasites (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum). This screening identified 29 molecules selectively active against bloodstream-form T. b. rhodesiense trypomastigotes, with 50% inhibitory concentrations (IC50) ranging from 0.12 to 10 μM, and 33 compounds active against the chloroquine- and pyrimethamine-resistant K1 strain of P. falciparum (IC50 range, 0.17 to 5 μM). In addition, seven compounds displayed activity against intracellular T. cruzi amastigotes in the same range as the reference drug benznidazole (IC50, 1.97 μM) but were also cytotoxic to L-6 cells, showing little selectivity for T. cruzi. None of the molecules tested showed interesting antileishmanial activity against axenic amastigotes of L. donovani. To our knowledge, this is the first report of the antitrypanosomal activity of molecules bearing the 4-aminopiperidine skeleton.

Efficient syntheses of new classes of regiochemically pure benzoporphyrin derivatives

Starting from rhodoporphyrin-SV dimethylo ester 4 and phylloerythrin methyl ester 5 new classes of isomerically pure benzoporphyrin analogues 7, 8, 11–17 were synthesized in high yields. These compounds have strong long wavelength absorptions in the red region and demonstrate activity against a transplanted mouse tumor.

Use of the chlorophyll derivative, purpurin-18, for syntheses of sensitizers for use in photodynamic therapy

Reactions of purpurin-18 methyl ester 6 with various nucleophiles have been investigated as a means for synthesis of sensitizers for use in photodynamic therapy of tumours. Use of butylamine as the nucleophile resulted in ring-opening of the purpurin-18 anhydride ring to give a monoamide-γ-carboxylic acid 8, the purpurin-imide 11, and the di-amide-γ-carboxylic acid 12. When lysine or its esters were used as nucleophile, then lysylamide-γ-carboxylic acids 18, 20 and 23 were obtained, along with the purpurin lysyl-imides 21 and 22. Esterification and hydrolysis of the various carboxy functions were investigated as a means for obtaining stable water-soluble sensitizers. Similar reactions between ornithine and purpurin-18 methyl ester gave the corresponding ornithyl-chlorin-p6 derivatives (e.g.31). The lysyl-chlorin-p618 was shown (in separate work) to be a highly effective tumour sensitizer.

Synthesis, structure (NMR and mass spectrometry) and conformational analysis of heterocyclic analogues of dibenzo[a,e]cycloocta-1,5-diene: 5,6,12,13-tetrahydrobispyrazolo[1,2-a:1′,2′-e][1,2,5,6]tetraazocinediium dihalides

Several 5,6,12,13-tetrahydrobispyrazolo[1,2-a:1′,2′-e][1,2,5,6] tetraazocinediium dihalides 4a–d and 8 are prepared from pyrazole, 3,5-dimethylpyrazole, 4-(1-adamantyl)pyrazole and campho[2,3-c]pyrazole by stepwise alkylation with 1,2-dibromoethane or 1,2-dichloroethane. Their structural characterization has been achieved by NMR and mass spectrometry. Dynamic NMR spectroscopy allowed the measurement of the barrier for the chair–chair interconversion in the case of the parent compound 4a and the 1,3,8,10-tetramethyl derivative 4b. These barriers as well as the preferred chair conformation are rationalized through semi-empirical and molecular mechanics calculations with regard to dibenzo[a,e]cycloocta-1,5-diene. The study of doubly charged bispyrazolium salts allows demonstration of their reduction by addition of a hydride ion [C+++ H–→(C + H)+] during FABMS experiments.

The structure of 1,1,3-trimethyl-Δ2-pyrazolinium perchlorate: An X-ray crystallographic and GIAO/DFT multinuclear NMR study

The crystal and molecular structure of 1,1,3-trimethyl-Δ2-pyrazolinium perchlorate has been determined and compared with those of other pyrazolinium salts (both 1,1 and 1,2-substituted). Reported 13C and 15N chemical shifts for a series of related pyrazolines have been compared with GIAO/DFT calculations, with excellent agreement. The combination of the biological properties of pyrazolines with those of the perchlorate anion in the same molecule will be discussed.

Cannabidiol skews biased agonism at cannabinoid CB1 and CB2 receptors with smaller effect in CB1-CB2 heteroreceptor complexes

Graphical abstract Figure. No Caption available. ABSTRACT Currently, biased agonism is at the center stage of drug development approaches. We analyzed effects of a battery of cannabinoids plus/minus cannabidiol (CBD) in four functional parameters (cAMP levels, phosphorylation of extracellular signal–regulated kinases (ERK1/2), &bgr;‐arrestin recruitment and label‐free/DMR) in HEK‐293T cells expressing cannabinoid receptors, CB1 or CB2, or CB1‐CB2 heteroreceptor complexes. In all cases two natural agonists plus two selective synthetic agonists were used. Furthermore, the effect of cannabidiol, at a dose (100 nM) that does not allow significant binding to the orthosteric center of either receptor, was measured. From the huge amount of generated data, we would like to highlight that the two psychotropic molecules (&Dgr;9‐tetrahydrocannabinol/THC and CP‐55940) showed similar bias in CB1R and that the bias of THC was particularly relevant toward MAPK pathway. Furthermore, THC did not activate the Gi protein coupled to CB2R. Interestingly, the biased agonism was reduced when assays were performed in cells expressing the two receptors, thus suggesting that the heteromer allows less functional selectivity. In terms of cannabidiol action, the phytocannabinoid altered the functional responses, likely by allosteric means, and modified potency, agonist IC50/EC50 values and biased agonism in qualitative and/or quantitative different ways depending on the agonist. The effect of cannabidiol on anandamide actions on both cannabinoid receptors was particularly noteworthy as was significantly different from that of other compounds. Results are a compendium of data on biased agonism on cannabinoid receptors in the absence and presence of cannabidiol. In addition, for the first time, GPCR biased agonism is characterized in an heteromeric context.