Optimization of isochromanone based urotensin II receptor agonists

A series of novel isochromanone based urotensin II receptor agonists have been synthesized and evaluated for their activity using a functional cell based assay (R-SAT). Several potent and efficacious derivatives were identified with 3-(3,4-dichlorophenyl)-6,7-dimethyl-3-(2-dimethylaminoethyl)isochroman-1-one (28) being the most potent compound showing an EC₅₀-value of 51 nM, thereby being the most potent compound so far within the isochromanone series. In addition, two other heterocyclic systems (isochromanes and tetrahydroisoquinolinones) were investigated and these derivatives were found to be both potent and efficacious. The activity of the isochromane derivatives implies that the carbonyl group of the isochromanone is not necessary for activity. Furthermore it was found that the geometry of the heterocycles was more important for receptor interaction than the composition of the heteroatoms present.     

Novel malonamide derivatives as potent kappa opioid receptor agonists

A novel series of malonamide derivatives was synthesized. These amides were shown to be potent and selective kappa opioid receptor agonists.     

Novel pyridine derivatives as potent and selective CB2 cannabinoid receptor agonists

Replacement of the phenyl ring in our previous (morpholinomethyl)aniline carboxamide cannabinoid receptor ligands with a pyridine ring led to the discovery of a novel chemical series of CB₂ ligands. Compound 3, that is, 2,2-dimethyl-N-(5-methyl-4-(morpholinomethyl)pyridin-2-yl)butanamide was identified as a potent and selective CB₂ agonist exhibiting in vivo efficacy after oral administration in a rat model of neuropathic pain.     

Novel phenylamino acetamide derivatives as potent and selective kappa opioid receptor agonists

A novel series of phenylamino acetamide derivatives was synthesized. These amides were shown to be potent and selective kappa opioid receptor agonists.     

Novel delta opioid receptor agonists with oxazatricyclodecane structure showing potent agonistic activities

We recently reported oxazatricyclodecane derivatives 1 as δ opioid receptor (DOR) agonists having a novel chemotype, but their DOR agonistic activities were relatively low. Based on the working hypothesis that the dioxamethylene moiety in 1 may be an accessory site and that it may interfere with the sufficient conformational change of the receptor required for exerting the full agonistic responses, we designed and synthesized new oxazatricyclodecane derivatives 2–4 lacking the dioxamethylene moiety. As we expected, the designed compounds 2–4 showed pronouncedly improved agonistic activities for the DOR. Compound 2a with the 17-cyclopropylmethyl substituent was a potent agonist with the highest selectivity for the DOR and was expected to be a lead compound for novel and selective DOR agonists.     

Novel and potent human and rat beta3-adrenergic receptor agonists containing substituted 3-indolylalkylamines

A novel series of 2-(3-indolyl)alkylamino-1-(3-chlorophenyl)ethanols was prepared and evaluated for in vitro ability to stimulate cAMP production in Chinese hamster ovary cells expressing cloned human beta(3)-AR. The optically active 30a was found to be the most potent and selective human beta(3)-AR agonist in this series with an EC(50) value of 0.062nM. In addition, 30a selectivity for human beta(3)-AR was 210-fold and 103-fold that for human beta(2)-AR and beta(1)-AR, respectively. Furthermore, 30a showed potent agonistic activity at rat beta(3)-AR.     

Identification of CXCR3 receptor agonists in combinatorial small-molecule libraries

In a high-throughput screen of four million compounds from combinatorial libraries for small-molecule modulators of the chemokine receptor CXCR3, two classes of receptor agonists, based on tetrahydroisoquinoline and piperidinyl diazepanone templates, were identified. Several of these compounds stimulated calcium flux in HEK293 cells expressing the recombinant human CXCR3 receptor with efficacies and kinetics similar to those of native ligand CXCL11/I-TAC and stimulated chemotaxis of activated human T-cells. The agonist small molecules also inhibited binding of another CXCR3 ligand, CXCL10/IP-10, to the receptor. The response to small-molecule agonists was inhibited by a CXCR3-specific small-molecule antagonist previously identified within the same combinatorial compound collection but structurally unrelated to the agonists. Remarkably, while other, non-amino acid substituents were present in the majority of the library compounds screened, the agonists from both classes contained a positively charged amino acid component, with preference for Arg>Lys, as well as a hydrophobic component.     

Genetic variations at urotensin II and urotensin II receptor genes and risk of type 2 diabetes mellitus in Japanese

Urotensin II is among the most potent vasoactive hormones known and the urotensin II (UTS2) gene is localized to 1p36-p32, one of the regions reported to show possible linkage with type 2 diabetes in Japanese. When we surveyed genetic polymorphisms in the UTS2 and urotensin II receptor (GPR14) gene, we identified two SNPs with amino acid substitutions (designated T21M and S89N and an SNP in the promotor region (-605G>A) of the UTS2 gene, and two SNPs in the non-coding region of the GPR14 gene. We then studied these three SNPs in the UTS2 gene and two SNPs in the GPR14 gene in 152 Japanese subjects with type 2 diabetes mellitus and two control Japanese populations. The allele frequency of 89N was significantly higher in type 2 diabetic patients than in both elderly normal subjects (P = 0.0018) and subjects with normal glucose tolerance (P = 0.0011), whereas the allele frequency of T21M and -605G>A in the UTS2 gene and those of two SNPs in the GPR14 gene were essentially identical in these three groups. Furthermore, in the subjects with normal glucose tolerance, 89N was associated with significantly higher insulin levels on oral glucose tolerance test, suggesting reduced insulin sensitivity in subjects with 89N. These results strongly suggest that subjects with S89N in the UTS2 gene are more insulin-resistant and thus more susceptible to type 2 diabetes mellitus development.     

New potent and selective A1 adenosine receptor agonists

Thiirane analogs of ENAdo have been synthesised and found to be extremely potent and selective A(1) adenosine receptor agonists.     

Novel 5-aryl-1,3-dihydro-indole-2-thiones. potent,orally active progesterone receptor agonists

During the course of our studies on 3,3-disubstituted-5-aryloxindoles derived progesterone receptor (PR) antagonists we discovered that changing the amide funtionality to a thio-amide resulted in compounds displaying potent PR agonist activity. In this communication, the synthesis, structure activity relationships (SAR) and in vivo activity of various 5-arylthio-oxindoles will be discussed.     

Novel morpholine ketone analogs as potent histamine H3 receptor inverse agonists with wake activity

Structure-activity relationship on a novel ketone class of H(3)R antagonists/inverse agonists is disclosed. Compound 4 showed excellent target potency, selectivity and brain penetration. Evaluation of antagonist 4 in the rat EEG/EMG model demonstrated robust wake activity thereby establishing preclinical proof of concept.     

Novel benzodifuran analogs as potent 5-HT2A receptor agonists with ocular hypotensive activity

A series of 8-substituted benzodifuran analogs was prepared and evaluated for 5-HT(2A) receptor binding and activation. Several compounds containing ether and ester functionality were found to be potent agonists. Topical ocular administration of 5, 18, and 25 effectively reduced intra-ocular pressure in the hypertensive cynomolgus monkey eye in the range of 25-37%.     

Peripheral benzodiazepine receptor agonists exhibit potent antiapoptotic activities

The peripheral benzodiazepine receptor (PBR) has been implicated in several mitochondrial functions but the exact physiological role of this receptor is still under debate. Since the mitochondria have been attributed a central role in cell death, we have determined the effects of various PBR agonists and antagonists on the apoptosis of the human lymphoblastoid cell line U937. On this cell type, the PBR agonist Ro5-4864 was found to strongly protect the cells against apoptosis induced by TNFalpha. The antiapoptotic effect of PBR agonists was due to a selective interaction with the PBR as demonstrated by: (1) a close correlation between the antiapoptotic activity of various PBR agonists and their respective affinity for the PBR determined on the same cells, (2) a lack of effect of central benzodiazepine receptors agonists such as clonazepam on cell survival, (3) the lack of an antiapoptotic activity of Ro5-4864 on wild-type Jurkat cells (lacking the PBR receptor) and the reappearance of this effect on PBR-transfected Jurkat cells, and (4) the blockade of the antiapoptotic effect of PBR agonists by a selective PBR antagonist. The present results therefore indicate that PBR agonists are potent antiapoptotic compounds and show that this effect might represent a major function for this enigmatic receptor.     

Novel tricyclic pyrazolopyrimidines as potent and selective GPR119 agonists

Systematic SAR optimization of the GPR119 agonist lead 1, derived from an internal HTS campaign, led to compound 29. Compound 29 displays significantly improved in vitro activity and oral exposure, leading to GLP1 elevation in acutely dosed mice and reduced glucose excursion in an OGTT study in rats at doses ⩾10 mg/kg.     

Haplotypes in the urotensin II gene and urotensin II receptor gene are associated with insulin resistance and impaired glucose tolerance

We studied single nucleotide polymorphisms (SNPs) and haplotypes in the urotensin-II (UTS2) and urotensin-II receptor gene (UTS2R) in Hong Kong Chinese (224 hypertensive and 306 normotensive unrelated subjects) and their relation to hypertension and the metabolic syndrome. For UTS2, the GGT haplotype (-605G, 143G and 3836T) was associated with higher plasma level of U-II and insulin, and higher homeostasis model assessment of insulin resistance index and beta-cell function. For UTS2R, the AC haplotype (-11640A and -8515C) was associated with higher 2 h plasma glucose after a 75 g oral glucose load. Therefore, U-II and its receptor may play a role in insulin resistance.     

Biological properties and functional determinants of the urotensin II receptor

The urotensin II receptor (UT) is a member of the G protein-coupled receptor (GPCR) family and binds the cyclic undecapeptide urotensin II (U-II) as well as the octapeptide urotensin II-related peptide (URP). The active UT mediates pleiotropic effects through various signal transduction pathways, including coupling to G proteins and activating the mitogen-activated protein kinase pathway. Several highly conserved residues and motifs of class A GPCRs that are important for activity are found in UT. This review highlights some of the putative roles of these motifs in the binding, activation and desensitization of UT.     

Transformation of mu-opioid receptor agonists into biologically potent mu-opioid receptor antagonists

N-Allylation (-CH(2)-CHCH(2)) of [Dmt(1)]endomorphins yielded the following: (i) [N-allyl-Dmt(1)]endomorphin-2 (Dmt=2',6'-dimethyl-l-tyrosine) (12) and [N-allyl-Dmt(1)]endomorphin-1 (15) (K(i)mu=0.45 and 0.26nM, respectively) became mu-antagonists (pA(2)=8.59 and 8.18, respectively) with weak delta-antagonism (pA(2)=6.32 and 7.32, respectively); (ii) intracerebroventricularly administered 12 inhibited morphine-induced CNS-mediated antinociception in mice [AD(50) (0.148ng/mouse) was 16-fold more potent than naloxone], but not spinal antinociception, and (iii) 15 reversed the alcohol-elevated frequency in spontaneous inhibitory post-synaptic currents (IPSC) in hippocampal CA1 pyramidal cells in rat brain slices (P=0.0055). Similarly, N-allylation of the potent mu-opioidmimetic agonists, 1,6-bis-[H-Dmt-NH]-hexane and 3,6-bis-[Dmt-NH-propyl]-2(1H)-pyrazinone, converted them into mu-antagonists (pA(2)=7.23 and 7.17 for the N-allyl-derivatives 17 and 19, respectively), and exhibited weak delta-antagonism. Thus, N-allylation of Dmt containing opioid peptides or opioidmimetics continues to provide a facile means to convert selective mu-opioid agonists into potent mu-opioid antagonists.     

Identification of potent phenyl imidazoles as opioid receptor agonists

Using previously reported opioid receptor (OR) agonist analogs 4a-c as starting points, the structure-activity relationship (SAR) for their related series has been further refined. This SAR study has led to the identification of 2,6-di-Me-Tyr (DMT) analogs 4h and 4j as the most potent OR agonist within the series. In addition, it was discovered that 4-(aminocarbonyl)-2,6-dimethyl-Phe is a reasonable bioisostere surrogate for the DMT moiety, as supported by the OR activities of compounds 4x and 4y.