Rationale-Identification of behaviors specifically mediated by the dopamine D2 and D3 receptors would allow for the determination of in vivo receptor selectivity and aide the development of novel therapeutics for dopamine-related diseases.Objectives-These studies were aimed at evaluating the specific receptors involved in the mediation of D2/D3 agonist-induced yawning and hypothermia.Correspondence to: James H. Woods. NIH Public AccessAuthor Manuscript Psychopharmacology (Berl) Methods-The relative potencies of a series of D2-like agonists to produce yawning and hypothermia were determined. The ability of D3-and D2-selective antagonists to inhibit the induction of yawning and hypothermia were assessed, and a series of D2/D3 antagonists were characterized with respect to their ability to alter yawning induced by a low and high dose of PD-128,907 as well as sumanirole-induced hypothermia.Results-D3-preferring agonists induced yawning at lower doses than those required to induce hypothermia, and the D2-preferring agonist, sumanirole, induced hypothermia at lower doses than were necessary to induce yawning. The rank order of D3 selectivity was pramipexole > PD-128,907 = 7-OH-DPAT = quinpirole = quinelorane > apomorphine = U91356A. Sumanirole had only D2 agonist effects. PG01037, SB-277011A and U99194 were all D3-selective antagonists, whereas haloperidol and L-741,626 were D2-selective antagonists and nafadotride's profile of action was more similar to the D2 antagonists than to the D3 antagonists.Conclusions-D3 and D2 receptors have specific roles in the mediation of yawning and hypothermia, respectively, and the analysis of these effects allow inferences to be made regarding the selectivity of D2/D3 agonists and antagonists with respect to their actions at D2 and D3 receptors.

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Derivatives of the highly selective kappa-opioid receptor antagonist GNTI (2a) have been prepared. Binding and functional studies conducted on cloned human opioid receptors expressed in Chinese hamster ovarian (CHO) cells suggested that adding a benzyl or a substituted benzyl group to the guanidino moiety led, in general, to a retention of high kappa-affinity and antagonist potency. Disubstitution of the guanidino moiety led to reduced kappa-selectivity.

Tumor blood vessels are an important emerging target for anticancer therapy. Here, we characterize the in vitro antiproliferative and antiangiogenic properties of the synthetic small molecule, 7-ethoxy-4-(3,4,5-trimethoxybenzyl)isoquinolin-8-amine dihydrochloride, EHT 6706, a novel microtubule-disrupting agent that targets the colchicine-binding site to inhibit tubulin polymerization. At low nM concentrations, EHT 6706 exhibits highly potent antiproliferative activity on more than 60 human tumor cell lines, even those described as being drug resistant. EHT 6706 also shows strong efficacy as a vascular-disrupting agent, since it prevents endothelial cell tube formation and disrupts pre-established vessels, changes the permeability of endothelial cell monolayers and inhibits endothelial cell migration. Genome-wide transcriptomic analysis of EHT 6706 effects on human endothelial cells shows that the antiangiogenic activity elicits gene deregulations of antiangiogenic pathways. These findings indicate that EHT 6706 is a promising tubulin-binding compound with potentially broad clinical antitumor efficacy.

Indolic N-benzylation of naltrindole reportedly extends the duration of delta-opioid receptor (DOR) antagonism. Similar modification of the kappa-opioid receptor (KOR) antagonist norBNI (1a) and its 17,17'-diNMe analogue (1d), a low potency mu-opioid receptor (MOR) partial agonist, was found to affect predominantly their MOR activity. When administered systemically in mouse antinociceptive assays, N-benzyl-norBNI (1b) had only MOR agonist activity of relatively short duration whereas on central administration it had only a KOR-antagonist action of extremely long duration.

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Among cytotoxics commonly used for cancer treatment, microtubule-targeting agents harbor a broad clinical anti-tumor efficacy. Microtubule-targeting agents act by their direct cytotoxic actions on tumor cells but also by their anti-angiogenic and vascular-disrupting actions. In contrast to classical antiangiogenic agents, vascular disrupting agents can, at the same time, block cell survival, prevent the formation of new vessels and damage the existing tumor vasculature. Here we describe EHT 6706, the current lead compound of a novel chemical class of tubulin targeting agents. EHT 6706 inhibits in a dose-dependent manner microtubule formation in an in vitro tubulin polymerization assay. EHT 6706 binds at or near the colchicine binding site of the tubulin-colchicine complex, hence displacing the [3]H-colchicine tracer. This binding competition is comparable to that of combretastain A-4, an established colchicine site binder with a higher affinity for tubulin than colchicine. At low concentrations, EHT 6706 decreases the amount of microtubular materials and induces alteration in tumor cell morphology. Perturbing microtubule dynamics with EHT 6706 halts the rapid cancer cells division by blocking cells in the metaphase/anaphase transition of the cell cycle and leads to apoptosis. EHT 6706 exhibits broad cytotoxicity in vitro with potency at sub-nanomolar/low nanomolar concentrations (0.3-10nM) in multiple cancer types (more than 60 cell lines, including the NCI60 panel) such as breast, melanoma, colorectal, renal, ovarian, non-small cell lung, leukaemia, as well as pancreatic cancer cells. EHT 6706 exerts this growth inhibition of human tumor cells independently of the type of main multidrug resistance mechanisms (ABC transporter MDR-1 (Pgp-1), MRP-1…). Furthermore, EHT 6706 retains cytotoxic activity against all of the resistant cell lines tested (combretastatin, vinblastin, imatinib), thus indicating the potential of this agent for the treatment of resistant tumors. EHT 6706 carries a potential for enhancing antitumor effects of radiation. In H460 and MiaPaca2 cell lines, indeed, EHT 6706 treatment inhibits clonogenic survival synergistically with ionizing radiation and exerts additive inhibition of proliferation when given in combination with conventional chemotherapeutic agents. Finally, in vitro experiments demonstrate that EHT 6706 has anti-angiogenic and vascular disrupting effects. Endothelial cell tube formation inhibition, pre-established vessels disruption, and vascular permeability increase were observed in a concentration- and time-dependent manner. These studies demonstrate that EHT 6706 has potent in vitro efficacy as a novel tubulin-targeted anti-proliferative and anti-vascular agent. EHT 6706 is a candidate for in vivo pharmacokinetic and efficacy studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2794. doi:1538-7445.AM2012-2794

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