Full Agonist Activity Research Articles

Synthesis and biological evaluation of 5-nitropyrimidine analogs with azabicyclic substituents as GPR119 agonists

5-Nitropyrimidine analogs substituted with conformationally restricted azabicyclic amines and alcohols were prepared and evaluated their agonistic activity against human GPR119. The analogs bearing endo-azabicyclic amines and alcohols (7, 8, 11, and 12) exhibited full agonistic activities while the analogs with exo-azabicyclic amines and alcohols were proved as partial agonists (9, 10, 13, and 14) regardless of their EC50 values. 5-Nitropyrimidine analogs with (2-fluoro-4-methylsulfonyl)phenylamino group (8, 10, 12, 14) showed more potent GPR119 activation activities than the analogs without fluorine in all cases (7, 9, 11, 13).

[Dmt1]N/OFQ(1–13)‐NH2: a potent nociceptin/orphanin FQ and opioid receptor universal agonist

Intrathecally (i.t.) administered nociceptin/orphanin FQ (N/OFQ) evokes antinociceptive effects in rodents. Recent studies in monkeys demonstrated that i.t. co-application of N/OFQ and morphine elicits synergistic antinociceptive actions suggesting mixed N/OFQ peptide (NOP) and μ opioid receptor agonists as innovative spinal analgesics. Thus, novel N/OFQ related peptides were synthesized in order to identify and pharmacologically characterize a mixed NOP/ μ opioid receptor agonist. The following in vitro assays were used: calcium mobilization in cells expressing the human NOP or classical opioid receptors and chimeric G proteins, receptor and [(35)S]-GTPγS binding, [(35)S]-GTPγS binding in rat spinal cord membranes, guinea pig ileum bioassay. In vivo experiments were performed in monkeys using the tail withdrawal assay. From calcium mobilization studies [Dmt(1)]N/OFQ(1-13)-NH(2) was selected as the most potent and least selective compound. The mixed NOP/opioid full agonist activity and high affinity of [Dmt(1)]N/OFQ(1-13)-NH(2) was confirmed at human recombinant receptors in receptor binding, calcium mobilization and/or [(35)S]-GTPγS binding studies, at rat spinal cord receptors in [(35)S]-GTPγS binding experiments, and at guinea pig receptors inhibiting neurogenic contractions in the ileum. In vivo in the tail withdrawal assay in monkeys i.t. [Dmt(1) ]N/OFQ(1-13)-NH(2) was able to elicit robust and long-lasting antinociceptive effects. Collectively, these results demonstrate that [Dmt(1)]N/OFQ(1-13)-NH(2) behaves as NOP/opioid receptor universal agonist and substantiate the suggestion that such mixed ligands are worthy of development as innovative spinal analgesics.

Magnolia Extract, Magnolol, and Metabolites: Activation of Cannabinoid CB2 Receptors and Blockade of the Related GPR55.

The bark of Magnolia officinalis is used in Asian traditional medicine for the treatment of anxiety, sleeping disorders, and allergic diseases. We found that the extract and its main bioactive constituents, magnolol and honokiol, can activate cannabinoid (CB) receptors. In cAMP accumulation studies, magnolol behaved as a partial agonist (EC50 = 3.28 μM) with selectivity for the CB2 subtype, while honokiol was less potent showing full agonistic activity at CB1 and antagonistic properties at CB2. We subsequently synthesized the major metabolites of magnolol and found that tetrahydromagnolol (7) was 19-fold more potent than magnolol (EC50 CB2 = 0.170 μM) exhibiting high selectivity versus CB1. Additionally, 7 behaved as an antagonist at GPR55, a CB-related orphan receptor (K B = 13.3 μM, β-arrestin translocation assay). Magnolol and its metabolites may contribute to the biological activities of Magnolia extract via the observed mechanisms of action. Furthermore, the biphenylic compound magnolol provides a simple novel lead structure for the development of agonists for CB receptors and antagonists for the related GPR55.

Selective estrogen receptor-beta (SERM-beta) compounds modulate raphe nuclei tryptophan hydroxylase-1 (TPH-1) mRNA expression and cause antidepressant-like effects in the forced swim test

Estrogen acts through two molecularly distinct receptors termed estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) which bind estradiol with similar affinities and mediate the effects of estrogen throughout the body. ERα plays a major role in reproductive physiology and behavior, and mediates classic estrogen signaling in such tissues as the uterus, mammary gland, and skeleton. ERβ, however, modulates estrogen signaling in the ovary, the immune system, prostate, gastrointestinal tract, and hypothalamus, and there is some evidence that ERβ can regulate ERα activity. Moreover, ERβ knockout studies and receptor distribution analyses in the CNS suggest that this receptor may play a role in the modulation of mood and cognition. In recent years several ERβ-specific compounds (selective estrogen receptor beta modulators; SERM-beta) have become available, and research suggests potential utility of these compounds in menopausal symptom relief, breast cancer prevention, diseases that have an inflammatory component, osteoporosis, cardiovascular disease, and inflammatory bowel disease, as well as modulation of mood, and anxiety. Here we demonstrate an antidepressant-like effect obtained using two SERM-beta compounds, SERM-beta1 and SERM-beta2. These compounds exhibit full agonist activity at ERβ in a cell based estrogen response element (ERE) transactivation assay. SERM-beta1 and 2 are non-proliferative with respect to breast as determined using the MCF-7 breast cancer cell-based assay and non-proliferative in the uterus as determined by assessing the effects of SERM-beta compounds on immature rat uterine weight and murine uterine weight. In vivo SERM-beta1 and 2 are brain penetrant and display dose dependent efficacy in the murine dorsal raphe assays for induction of tryptophan hydroxylase mRNA and progesterone receptor protein. These compounds show activity in the murine forced swim test and promote hippocampal neurogenesis acutely in rats. Taken together these data suggest that ERβ may play an important role in modulating mood and the ERβ specific compounds described herein will be useful tools for probing the utility of an ERβ agonist for treating neuroendocrine-related mood disturbance and menopausal symptoms.

Functional investigation of β-adrenoceptors in human isolated detrusor focusing on the novel selective β3-adrenoceptor agonist KUC-7322

This study aimed to characterize the β-adrenoceptor (β-AR) subtype mediating relaxation of isolated human bladder strips and to explore relaxation by the novel β3-AR-selective agonist KUC-7322 for its relaxant effect on the human isolated detrusor and for its effect on the carbachol (CCh)-induced contractile response. In two parallel studies, relaxation of isolated human bladder strips was tested for the β-AR agonists isoproterenol, clenbuterol, BRL 37344, and KUC-7322. For the isoproterenol and KUC-7322 responses, antagonism by CGP 20712A, ICI 118551, and SR59230A was determined. The potency and efficacy of the reference agonists for detrusor relaxation was in line with their known β3-AR activity. KUC-7322 relative to isoproterenol was a full agonist with a pEC(50) of 5.95 ± 0.09 and 5.92 ± 0.11 in the two studies. SR59230A exhibited antagonism of the expected potency against isoproterenol (apparent pK (B) 7.2) but not against KUC-7322. Neither isoproterenol nor KUC-7322 nor forskolin significantly attenuated CCh-induced contraction. These results suggest that KUC-7322 displays full agonistic activity in relaxing the human detrusor without inhibiting the contraction induced by cholinergic stimulation. These characteristics, if proven in vivo, may be beneficial for the treatment of overactive bladder, as increased bladder capacity with a negligible effect on voiding contractions may be anticipated.

Butyl Pocket Formation in the Vitamin D Receptor Strongly Affects the Agonistic or Antagonistic Behavior of Ligands

Previously, we reported that 22S-butyl-25,26,27-trinor-1α,24-dihydroxyvitamin D(3)2 represents a new class of antagonist for the vitamin D receptor (VDR). The crystal structure of the ligand-binding domain (LBD) of VDR complexed with 2 showed the formation of a butyl pocket to accommodate the 22-butyl group and insufficient interactions between ligand 2 and the C-terminus of VDR. Here, we designed and synthesized new analogues 5a-c and evaluated their biological activities to probe whether agonistic activity is recovered when the analogue restores interactions with the C-terminus of VDR. Analogues 5a-c exhibited full agonistic activity in transactivation. Interestingly, 5c, which bears a 24-diethyl group, completely recovered agonistic activity, although 3c and 4c act as an antagonist and a weak agonist, respectively. The crystal structures of VDR-LBD complexed with 3a, 4a, 5a, and 5c were solved, and the results confirmed that butyl pocket formation in VDR strongly affects the agonistic or antagonistic behaviors of ligands.

Dmt1]N/OFQ(1‐13)‐NH2, a potent NOP/MOP receptor mixed agonist

i.t. nociceptin/orphanin FQ (N/OFQ) evokes antinociceptive effects in rodents. Studies in monkeys demonstrated that i.t. coapplication of N/OFQ and morphine elicits synergistic antinociceptive actions. Novel N/OFQ related peptides were synthesised in order to identify and characterize mixed NOP/MOP agonists. The following in vitro assays were used: Ca2+ mobilization in cells expressing hNOP or hMOP receptors and the chimeric protein Gαqi5, receptor and [35S]GTPS binding, guinea pig ileum bioassay. In vivo experiments were performed in mice and monkeys using the tail withdrawal assay. From Ca2+ mobilization studies [Dmt1]N/OFQ(1‐13)NH2 was selected as the most potent and least selective compound. The mixed NOP/MOP full agonist activity and high affinity of [Dmt1]N/OFQ(1‐13)NH2 was confirmed at recombinant receptors in receptor and [35S]GTPS binding studies, at rat spinal cord receptors in [35S]GTPS binding experiments, and in the guinea pig ileum. In vivo in mice and monkeys i.t. morphine and N/OFQ evoked similar antinociceptive effects. [Dmt1]N/OFQ(1‐13)NH2 was also able to elicit a robust antinociceptive action being more potent than N/OFQ (by 30 fold) and morphine (by 3 fold). These results demonstrate that [Dmt1]N/OFQ(1‐13)NH2 behaves as mixed NOP/MOP agonist and substantiate the proposal that such mixed ligands are worthy of development as spinal analgesics.

Identification of a novel dopaminergic agonist that selectively activates the D2 dopamine receptor

In order to identify novel ligands with selectivity for the D2 dopamine (DA) receptor (DAR), we have interrogated small molecule chemical libraries using live cell functional assays and high throughput screening (HTS) techniques. Our primary HTS assay involves D2 DAR activation of a chimeric G protein, Gqi5, which links D2 DAR activation to Ca2+ mobilization. This process led to the identification of a ligand (compound A) that selectively activates the D2 DAR in comparison with other DAR subtypes. We found that compound A exhibits full agonist activity with EC50 values ranging from 100 nM – 1 μM using three different functional assays for the D2 DAR; Ca2+ mobilization, inhibition of cAMP accumulation, and β‐arrestin recruitment. Using β‐arrestin recruitment assays to compare with other DARs, we found that compound A has no activity at D1‐like DARs (D1 and D5), weak antagonist activity at D4 DARs (at concentrations > 10 μM), and either weak partial agonist (<20% of the DA response) or full antagonist activity at D3 DARs. Radioligand binding assays revealed that compound A exhibits Ki values of ~1 μM and ~100 nM for the D2 and D3 DARs, respectively. In summary, compound A is a full and selective agonist at the D2 DAR, although it is also functions as a D3 DAR antagonist. This is the first known compound that functionally discriminates between the D2 and D3 DARs and selectively activates the D2 DAR in the absence of D3 DAR activation.

D-Cycloserine: An Evolving Role in Learning and Neuroplasticity in Schizophrenia

As a partial agonist at the glycine site of the NMDA receptor, D-cycloserine (DCS) has been viewed as lacking potency to fully test the NMDA receptor hypofunction theory of schizophrenia. However, findings of full agonist activity at a subset of NMDA receptors that may have particular relevance to schizophrenia, plus a growing body of evidence demonstrating enhancement of learning and neuroplasticity in animal models, suggest novel therapeutic strategies with DCS in schizophrenia. Preliminary studies with once-weekly administration have supported this potential new role for DCS in schizophrenia by demonstrating benefit for negative symptoms, memory consolidation, and facilitation of cognitive behavioral therapy for delusions.

NOpiates: Novel Dual Action Neuronal Nitric Oxide Synthase Inhibitors with μ-Opioid Agonist Activity.

A novel series of benzimidazole designed multiple ligands (DMLs) with activity at the neuronal nitric oxide synthase (nNOS) enzyme and the μ-opioid receptor was developed. Targeting of the structurally dissimilar heme-containing enzyme and the μ-opioid GPCR was predicated on the modulatory role of nitric oxide on μ-opioid receptor function. Structure-activity relationship studies yielded lead compound 24 with excellent nNOS inhibitory activity (IC50 = 0.44 μM), selectivity over both endothelial nitric oxide synthase (10-fold) and inducible nitric oxide synthase (125-fold), and potent μ-opioid binding affinity, K i = 5.4 nM. The functional activity as measured in the cyclic adenosine monosphospate secondary messenger assay resulted in full agonist activity (EC50 = 0.34 μM). This work represents a novel approach in the development of new analgesics for the treatment of pain.

A Second Chance for a PPARγ Targeted Therapy?

### Antidiabetic Actions of a Non-Agonist PPARγ Ligand Blocking Cdk5-Mediated Phosphorylation Choi et al Nature . 2011;477:477–481. A new class of non-agonist ligands target the transcription factor PPARγ and promote expression of insulin-sensitizing adipokines. They have potent antidiabetic actions, yet they lack several of the adverse effects commonly associated with thiazolidinediones. The ligands may represent a new class of anti-diabetes medications that preserve the most beneficial effects of PPARγ activation without imparting major side effects, which have limited the clinical usefulness of thiazolidinediones . Once thought to be a magic bullet for the treatment of type 2 diabetes, thiazolidinedione (TZD) drugs such as rosiglitazone and pioglitazone are now recognized to have adverse effects, which have limited their clinical usefulness. TZDs were originally thought to improve insulin sensitivity by robustly activating the transcriptional activity of the ligand-activated nuclear receptor PPARγ. A study by the Spiegelman laboratory published in the July 22, 2010 issue of Nature revealed that rosiglitazone also inhibits the obesity-induced phosphorylation of PPARγ by the cyclin-dependent kinase 5 (Cdk5).1 The inhibition of CDK5-mediated phosphorylation of PPARγ could also be mediated by PPARγ ligands, which lack full agonist activity suggesting a novel action of TZDs on PPARγ. Now, in the September 22, 2011 issue of Nature , the same research team reports that a new class of PPARγ ligands, which do not act as classical agonists as they lack robust transcriptional activation, effectively block Cdk5-mediated phosphorylation of PPARγ.2 Importantly, these compounds have potent antidiabetic actions, but they do not cause fluid retention nor inhibit bone formation, major adverse effects of TZDs. The study provides an important proof-of-principle that new non-TZD drugs targeting PPARγ could be designed that preserve its most beneficial actions while eliminating its most detrimental side effects. PPARγ is the target of the TZD class of antidiabetic agents, which improves glycemic control by increasing sensitivity to insulin. An ideal type 2 diabetes drug …

Protein Engineered Variants of Hepatocyte Growth Factor/Scatter Factor Promote Proliferation of Primary Human Hepatocytes and in Rodent Liver

Hepatocyte growth factor/scatter factor (HGF/SF) stimulates hepatocyte DNA synthesis and protects against apoptosis; in vivo it promotes liver regeneration and reduces fibrosis. However, its therapeutic value is limited by its complex domain structure, high cost of production, instability, and poor tissue penetration due to sequestration by heparin sulfate proteoglycans (HSPGs). Using protein engineering techniques, we created a full-length form of HGF/SF (called HP21) and a form of the small, naturally occurring HGF/SF fragment, NK1 (called 1K1), which have reduced affinity for HSPG. We characterized the stability and proliferative and anti-apoptotic effects of these variants in primary human hepatocytes and in rodents. Analytical ultracentrifugation showed that 1K1 and NK1 were more stable than the native, full-length protein. All 4 forms of HGF/SF induced similar levels of DNA synthesis in human hepatocytes; 1K1 and NK1 required heparin, an HSPG analogue, for full agonistic activity. All the proteins reduced levels of Fas ligand-mediated apoptosis, reducing the activity of caspase-3/7 and cleavage of poly(adenosine diphosphate-ribose) polymerase. 1K1 was more active than NK1 in rodents; in healthy mice, 1K1 significantly increased hepatocyte DNA synthesis, and in mice receiving carbon tetrachloride, it reduced fibrosis. In rats, after 70% partial hepatectomy, daily administration of 1K1 for 5 days significantly increased liver mass and the bromodeoxyuridine labeling index compared with mice given NK1. 1K1, an engineered form of the small, naturally occurring HGF/SF fragment NK1, has reduced affinity for HSPG and exerts proliferative and antiapoptotic effects in cultured hepatocytes. In rodents, 1K1 has antifibrotic effects and promotes liver regeneration. The protein has better stability and is easier to produce than HGF/SF and might be developed as a therapeutic for acute and chronic liver disease.

Δ 9-Tetrahydrocannabinol attenuates MDMA-induced hyperthermia in rhesus monkeys

Background: Cannabis is commonly consumed by Ecstasy (3,4-methylenedioxymethamphetamine; MDMA) users, including as an intentional strategy to manipulate the drug experience. The most active psychoactive constituent in cannabis, Δ 9-tetrahydrocannabinol (THC), and other drugs with partial or full agonist activity at the CB 1 receptor, produces a reduction of body temperature in rodents. Reports show that administration of THC can attenuate temperature increases caused by MDMA in mice or rats; however, a recent study in humans shows that THC potentiates MDMA-induced temperature elevations. Relatively little scientific evidence on the thermoregulatory effects of THC in monkeys is available. Methods: The body temperature of male rhesus macaques was recorded after challenge with THC (0.1–0.3 mg/kg, i.m.) or combined challenge of THC with the CB 1 receptor antagonist SR141716 (Rimonabant; 0.3 mg/kg, i.m.) or combined challenge of THC (0.1, 0.3 mg/kg, i.m.) with MDMA (1.78 mg/kg p.o.) using minimally-invasive, implanted radiotelemetry techniques. Results: THC reduced the body temperature of monkeys in a dose-dependent manner with the nadir observed 3–5 h post-injection; however, an attenuation of normal circadian cooling was also produced overnight following dosing. Hypothermia induced by THC (0.3 mg/kg, i.m.) was prevented by Rimonabant (0.3 mg/kg, i.m.). Finally, 0.3 mg/kg THC (i.m.) attenuated the elevation of body temperature produced by MDMA for about 4 h after oral dosing. Conclusions: As with rodents THC produces a robust and lasting decrement in the body temperature of rhesus monkeys; this effect is mediated by the CB 1 receptor. THC also protects against the immediate hyperthermic effects of MDMA in monkeys in a dose-dependent manner. Nevertheless, a paradoxical attenuation of circadian cooling overnight after the THC/MDMA combination cautions that longer-term effects may be critical in assessing risks for the recreational user of cannabis in combination with MDMA.

N-Acetylfarnesylcysteine Is a Novel Class of Peroxisome Proliferator-activated Receptor γ Ligand with Partial and Full Agonist Activity in Vitro and in Vivo

The thiazolidedione (TZD) class of drugs is clinically approved for the treatment of type 2 diabetes. The therapeutic actions of TZDs are mediated via activation of peroxisome proliferator-activated receptor γ (PPARγ). Despite their widespread use, concern exists regarding the safety of currently used TZDs. This has prompted the development of selective PPARγ modulators (SPPARMs), compounds that promote glucose homeostasis but with reduced side effects due to partial PPARγ agonism. However, this also results in partial agonism with respect to PPARγ target genes promoting glucose homeostasis. Using a gene expression-based screening approach we identified N-acetylfarnesylcysteine (AFC) as both a full and partial agonist depending on the PPARγ target gene (differential SPPARM). AFC activated PPARγ as effectively as rosiglitazone with regard to Adrp, Angptl4, and AdipoQ, but was a partial agonist of aP2, a PPARγ target gene associated with increased adiposity. Induction of adipogenesis by AFC was also attenuated compared with rosiglitazone. Reporter, ligand binding assays, and dynamic modeling demonstrate that AFC binds and activates PPARγ in a unique manner compared with other PPARγ ligands. Importantly, treatment of mice with AFC improved glucose tolerance similar to rosiglitazone, but AFC did not promote weight gain to the same extent. Finally, AFC had effects on adipose tissue remodeling similar to those of rosiglitazone and had enhanced antiinflammatory effects. In conclusion, we describe a new approach for the identification of differential SPPARMs and have identified AFC as a novel class of PPARγ ligand with both full and partial agonist activity in vitro and in vivo.

Synthesis and structure–activity relationships of 4,5-fused pyridazinones as histamine H3 receptor antagonists

Three series of novel 4,5-fused pyridazinones were synthesized as histamine H(3) receptor antagonists. The 2,5,6,7-tetrahydrocyclopenta[d]pyridazin-1-one 5q and 5,6,7,8-tetrahydro-2H-phthalazin-1-one 5u displayed high affinity at both rat and human H(3) receptors, and showed potent antagonist and full inverse agonist activity in functional assays.

Distinct carbohydrate and lipid-based molecular patterns within lipopolysaccharides fromBurkholderia cepaciacontribute to defense-associated differential gene expression inArabidopsis thaliana

Lipopolysaccharides are structural components within the cell walls of Gram-negative bacteria. The LPSs as microbe-associated molecular pattern (MAMP) molecules can trigger defense-related responses involved in MAMP-triggered immunity and basal resistance in plants, presumably from an initial perception event. LPS from Burkholderia cepacia as well as two fragments, the glycolipid, lipid A and the polysaccharide (OPS-core) chain, were used to treat Arabidopsis thaliana seedlings to evaluate the eliciting activities of the individual LPS sub-domains by means of Annealing Control Primer-based Differential Display transcript profiling. Genes found to be up-regulated encode for proteins involved in signal perception and transduction, transcriptional regulation and defense - and stress responses. Furthermore, genes encoding proteins involved in chaperoning, secretion, protein-protein interactions and protein degradation were differentially expressed. It is concluded that intact LPS, as well as the two sub-components, induced the expression of a broad range of genes associated with perception and defense as well as metabolic reprogramming of cellular activities in support of immunity and basal resistance. Whilst the lipid A and OPS moieties were able to up-regulate sub-sets of defense-associated genes over the same spectrum of categories as intact LPS, the up-regulation observed with intact LPS was the more comprehensive, suggesting that the lipid A and glycan molecular patterns of the molecule act as partial agonists, but that the intact LPS structure is required for full agonist activity.

Identification of a High-Affinity Ligand That Exhibits Complete Aryl Hydrocarbon Receptor Antagonism

The biological functions of the aryl hydrocarbon receptor (AHR) can be delineated into dioxin response element (DRE)-dependent or -independent activities. Ligands exhibiting either full or partial agonist activity, e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin and α-naphthoflavone, have been demonstrated to potentiate both DRE-dependent and -independent AHR function. In contrast, the recently identified selective AHR modulators (SAhRMs), e.g., 1-allyl-3-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-1H-indazole (SGA360), bias AHR toward DRE-independent functionality while displaying antagonism with regard to ligand-induced DRE-dependent transcription. Recent studies have expanded the physiological role of AHR to include modulation of hematopoietic progenitor expansion and immunoregulation. It remains to be established whether such physiological roles are mediated through DRE-dependent or -independent pathways. Here, we present evidence for a third class of AHR ligand, "pure" or complete antagonists with the capacity to suppress both DRE-dependent and -independent AHR functions, which may facilitate dissection of physiological AHR function with regard to DRE or non-DRE-mediated signaling. Competitive ligand binding assays together with in silico modeling identify N-(2-(1H-indol-3-yl)ethyl)-9-isopropyl-2-(5-methylpyridin-3-yl)-9H-purin-6-amine (GNF351) as a high-affinity AHR ligand. DRE-dependent reporter assays, in conjunction with quantitative polymerase chain reaction analysis of AHR targets, reveal GNF351 as a potent AHR antagonist that demonstrates efficacy in the nanomolar range. Furthermore, unlike many currently used AHR antagonists, e.g., α-naphthoflavone, GNF351 is devoid of partial agonist potential. It is noteworthy that in a model of AHR-mediated DRE-independent function, i.e., suppression of cytokine-induced acute-phase gene expression, GNF351 has the capacity to antagonize agonist and SAhRM-mediated suppression of SAA1. Such data indicate that GNF351 is a pure antagonist with the capacity to inhibit both DRE-dependent and -independent activity.

Extending SAR of bile acids as FXR ligands: Discovery of 23- N-(carbocinnamyloxy)-3α,7α-dihydroxy-6α-ethyl-24-nor-5β-cholan-23-amine

Within our efforts in the discovery of novel potent and selective ligands for the FXR receptor, 23- N-(carbocinnamyloxy)-3α,7α-dihydroxy-6α-ethyl-24-nor-5β-cholan-23-amine was synthesized and evaluated for its ability to activate and modulate the biological response of the receptor. Alphascreen and RT-PCR revealed that the 6α-ethyl-24-norcholanyl-23-amine derivate behaves as full FXR agonist endowed with high binding affinity and efficacy, representing a promising lead candidate for further optimization. In addition, docking studies provide new insights into the molecular basis governing the partial and full agonist activity at FXR.

Ligand-based receptor tyrosine kinase partial agonists: new paradigm for cancer drug discovery?

Introduction: Receptor tyrosine kinases (RTKs) are validated targets for oncology drug discovery and RTK antagonists are available to treat human malignancies. Nonetheless, the development of RTK antagonists has lagged behind the development of agents that target GPCRs. In part, this is because it has been difficult to discover analogs of RTK agonists that function as antagonists.Areas covered: In this review the author describes ligands of ErbB receptors that function as partial agonists for these receptors and antagonize the activity of full agonists for these receptors. The author provides insights into the mechanisms by which these ligands function as antagonists and discuss how these insights can be translated into screens for novel small molecule- and antibody-based antagonists of ErbB receptors that hold potential as targeted cancer chemotherapeutics.Expert opinion: While there have been numerous key findings in this field, the identification of the structural basis of ligand functional specificity is still of the greatest importance. While it is true that, with some notable exceptions, peptide hormones and growth factors have not been good platforms for oncology drug discovery, addressing the fundamental issues of antagonistic partial agonists for RTKs has the potential of steering oncology drug discovery in new directions. Mechanism-based approaches are emerging to enable the discovery of small molecule and antibody RTK partial agonists that may antagonize RTK signaling and may hold promise as targeted cancer chemotherapeutics.

Synthesis and biological evaluation of new salvinorin A analogues incorporating natural amino acids

The synthesis and in vitro evaluation of a new series of salvinorin A analogues substituted at the C(2) position with natural amino acids is reported. Compound 12, containing Val, displayed high affinity and full agonist activity at the kappa-opioid receptor. Analogues with bulky and/or aromatic residues were inactive, showing the importance of size and electronegativity of C(2)-substituents for binding affinity of salvinorin A derivatives.