Vascular pharmacology of a novel cannabinoid-like compound, 3-(5-dimethylcarbamoyl-pent-1-enyl)-N-(2-hydroxy-1-methyl-ethyl)benzamide (VSN16) in the rat.

BACKGROUND AND PURPOSE: A putative novel cannabinoid receptor mediates vasorelaxation to anandamide and abnormal-cannabidiol and is blocked by O-1918 and by high concentrations of rimonabant. This study investigates VSN16, a novel water-soluble agonist, as a vasorelaxant potentially acting at non-CB1, non-CB2 cannabinoid receptors in the vasculature. EXPERIMENTAL APPROACH: VSN16 and some analogues were synthesized and assayed for vasodilator activity in the rat third generation mesenteric artery using wire myography. Also carried out with VSN16 were haemodynamic studies in conscious rats and binding studies to CB1 receptors of rat cerebellum. KEY RESULTS: VSN16 relaxed mesenteric arteries in an endothelium-dependent manner. The vasorelaxation was antagonized by high concentrations of the classical cannabinoid antagonists, rimonabant and AM 251, as well as by O-1918, an antagonist at the abnormal-cannabidiol receptor but not at CB1 or CB2 receptors. It did not affect [3H]CP55,940 binding to CB1 receptors in rat cerebellum. The vasorelaxation was not pertussis toxin-sensitive but was reduced by inhibition of nitric oxide synthesis, Ca(2+)-sensitive K+ channels (KCa) and TRPV1 receptors. In conscious rats VSN16 transiently increased blood pressure and caused a longer-lasting increase in mesenteric vascular conductance. Structure-activity studies on vasorelaxation showed a stringent interaction with the target receptor. CONCLUSIONS AND IMPLICATIONS: VSN16 is an agonist at a novel cannabinoid receptor of the vasculature. It acts on the endothelium to release nitric oxide and activate KCa and TRPV1. As it is water-soluble it might be useful in bringing about peripheral cannabinoid-like effects without accompanying central or severe cardiovascular responses.

Observations on the reactivity of thiyl radicals derived from 3,6-epidithiodiketopiperazine-2,5-diones and related congeners.

A range of thiyl radicals derived from the reduced form of epidithiodiketopiperazines (ETPs) act as polarity reversal catalysts for the hydrosilylation of an enol lactone but not for H-atom abstraction from a model ribose ester.

Solution-Phase parallel synthesis of 5-carboxamido 1-benzyl-3-(3-dimethylaminopropyloxy)-1H-pyrazoles as activators of soluble guanylate cyclase with improved oral bioavailability.

A lipophilicity constrained library of 5-carboxamido 1-benzyl-3-(3-dimethylaminopropyloxy)-1H-pyrazoles was prepared by solution-phase parallel synthesis with removal of acidic by-products using the strongly basic MP-carbonate resin. Compounds show both activation of soluble guanylate cyclase and inhibition of platelet aggregation. Compound 12 also shows 22% oral bioavailability in rats.

Discovery of 4-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)-oxazolidin-2-one (4991W93), a 5HT(1B/1D) receptor partial agonist and a potent inhibitor of electrically induced plasma extravasation.

Utilizing a pharmacophoric model of binding of 3-(2-aminoethyl)indoles to 5HT(1B/1D) receptors, we identified the 3-aminocyclobutyl group as a potential ethylamine isostere. A novel multidimensional chemometric approach was used to predict the intrinsic activity (degree of agonism) at the receptor. A qualitative model for pharmacokinetic properties was then used to guide the synthesis toward molecules likely to have oral bioavailability in humans. A novel synthetic route to 3-(3-dimethylaminocyclobutyl)indoles was developed. Analogues showed generally lower intrinsic activity at 5HT(1B/1D) receptors than their ethylamine counterparts. 4-[3-(trans-3-Dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)-oxazolidin-2-one (4991W93, 1) was identified as a partial agonist against 5HT(1B/1D) receptors, with low intrinsic activity. This molecule also has significant activity against 5HT(1F) receptors but is selective over other 5HT receptors. In addition this compound was found to be an exceptionally potent inhibitor of electrically induced plasma extravasation. Compound 1 may have utility in the treatment and prophylaxis of migraine.

Synthesis and biological evaluation of novel pyrazoles and indazoles as activators of the nitric oxide receptor, soluble guanylate cyclase.

Database searching and compound screening identified 1-benzyl-3-(3-dimethylaminopropyloxy)indazole (benzydamine, 3) as a potent activator of the nitric oxide receptor, soluble guanylate cyclase. A comprehensive structure-activity relationship study surrounding 3 clearly showed that the indazole C-3 dimethylaminopropyloxy substituent was critical for enzyme activity. However replacement of the indazole ring of 3 by appropriately substituted pyrazoles maintained enzyme activity. Compounds were evaluated for inhibition of platelet aggregation and showed a general lipophilicity requirement. Aryl-substituted pyrazoles 32, 34, and 43 demonstrated potent activation of soluble guanylate cyclase and potent inhibition of platelet aggregation. Pharmacokinetic studies in rats showed that compound 32 exhibits modest oral bioavailability (12%). Furthermore 32 has an excellent selectivity profile notably showing no significant inhibition of phosphodiesterases or nitric oxide synthases.

Isosteres of the DNA polymerase inhibitor aphidicolin as potential antiviral agents against human herpes viruses.

A variety of isosteres of the DNA polymerase inhibitor aphidicolin were synthesized as potential antiherpes agents. Modeling studies indicated that the bicyclooctane C, D rings of aphidicolin could be replaced by an aromatic moiety while maintaining the spatial arrangement of the hydroxyl group equivalent to the essential C18 hydroxyl group of aphidicolin. Of the racemic isosteres synthesized only 13, the compound with the greatest structural similarity to aphidicolin, showed any significant antiviral activity in primary assays. An enantioselective synthesis of the compound was carried out and the 4aS isomer 36 was shown to account for the observed antiviral activity noted against herpes simplex virus 1 and human cytomegalovirus.

Glucose transport in Acanthocheilonema viteae.

The uptake of glucose by Acanthocheilonema viteae was studied in vitro. The process was selective for the D-isomer and saturatable with a Km of 2 mM. The rate of glucose transport/utilization was inhibited by 2-deoxyglucose, mannose, 5-thioglucose and dipyridamole but, unlike mammalian systems, was not impaired by cytochalasin B, phloretin, phloridzin, 3-O-methylglucose and 4,6-ethylideneglucose. A potential chemotherapeutic advantage of selectively inhibiting filarial glucose transport exists for the following reasons. (1) The glucose transporter present in A. viteae was shown to be different from the one present in some mammalian systems. (2) Incubation under glucose-free conditions led to glycogen depletion, loss of motility and worm death. (3) Worms maintained in vitro for more than 18 h without glucose did not survive when implanted into gerbils.

The effect of two novel analogues of antimycin A on oxygen consumption and survival of filarial nematodes in vitro.

The effects of two novel analogues of antimycin A (BWA466C and BWA728C) on filarial oxygen consumption, energy generation and survival were investigated in vitro. For comparison, incubations were performed with a range of mitochondrial respiration inhibitors. All compounds tested (rotenone, antimycin A, KCN, oligomycin, CCCP, rafoxanide, BWA466C and BWA728C) inhibited oxygen uptake. The two analogues were less potent than antimycin A at impairing respiration of either filariae or beef heart submitochondrial particles. However, the two compounds affected motility and were lethal in vitro. Although the analogues affected oxygen uptake similarly to antimycin A itself, the levels of ATP were significantly lower than those noted in the presence of antimycin A. Glucose consumption and lactate output were markedly reduced by BWA466C and BWA728C. Glucose transport (measured as 2-deoxy-[2,6-3H]glucose) was reduced after treatment with BWA728C. It is likely that a combination of the effects on glucose transport and inhibition of oxidative pathways of carbohydrate metabolism may lead to worm death in vitro.

Structure-activity relationships of antifilarial antimycin analogues: a multivariate pattern recognition study.

The structure-activity relationships of a series of novel antifilarial antimycin A1 analogues have been investigated by using computational chemistry and multivariate statistical techniques. The physiochemical descriptors calculated in this way contained information which was useful in the classification of compounds according to their in vitro antifilarial activity. This approach generated a 53 parameter descriptor set, which was reduced with a multivariate pattern recognition package, ARTHUR. Regression analysis of the reduced set yielded several statistically significant regression equations; e.g.-log in vitro activity = 0.017 mp + 0.65 log P - 0.81ESDL10-7.33 (R = 0.9). With use of this equation, it was possible to make predictions for further untested analogues. The analysis indicated that membrane or lipid solubility is an important determinant in biological activity agreeing with the proposed primary mode of action of the compounds as disrupters of cuticular glucose uptake.