Discovery of ONO-8590580: A novel, potent and selective GABAA α5 negative allosteric modulator for the treatment of cognitive disorders.

The identification and SAR development of a series of negative allosteric modulators of the GABAA α5 receptor is described. This novel series of compounds was optimised to provide analogues with high GABAA α5 binding affinity, high α5 negative allosteric modulatory activity, good functional subtype selectivity and low microsomal turnover, culminating in identification of ONO-8590580.

Procoagulant and proinflammatory effects of red blood cells on lipopolysaccharide-stimulated monocytes.

BACKGROUND: We aimed to evaluate the mechanisms underlying the effects of red blood cells (RBCs) on the reactivity of monocytes to lipopolysaccharide (LPS) stimulation. METHODS: Measurements of tissue factor (TF) antigen and activity were performed on freshly isolated white blood cells (WBCs)/platelets resuspended in heparinized plasma, as well as cultured monocytic cells. RESULTS: In a dose-dependent manner, RBCs significantly enhanced LPS-induced TF activity and antigen levels in blood monocytes; potentiation of TF activity by both human and murine RBCs did not require the presence of neutrophils and/or platelets. We also measured the levels of monocyte chemotactic protein-1 (MCP-1), the key proinflammatory chemokine that binds to duffy antigen receptor for chemokines (DARC) on RBC surface, in plasma and RBC lysates after the incubation of RBCs with WBC/platelets; at the concentrations corresponding to normal blood counts, RBCs exerted a significant influence on the free plasma levels of MCP-1, with about two-thirds of detectable MCP-1 post-LPS stimulation being associated with RBCs. Critically, DARC-deficient murine RBCs failed to enhance LPS-induced TF activity, confirming the mechanistic significance of RBC-DARC. CONCLUSIONS: Our study reports a novel mechanism by which RBCs promote procoagulant and proinflammatory sequelae of WBC exposure to LPS, likely mediated by RBC-DARC in the microenvironment(s) that bring monocytes and RBCs in close proximity.

Genetic knockout and pharmacological blockade studies of the 5-HT7 receptor suggest therapeutic potential in depression.

The affinity of several antidepressant and antipsychotic drugs for the 5-HT7 receptor and its CNS distribution suggest potential in the treatment of psychiatric diseases. However, there is little direct evidence of receptor function in vivo to support this. We therefore evaluated 5-HT7 receptors as a potential drug target by generating and assessing a 5-HT7 receptor knockout mouse. No difference in assays sensitive to potential psychotic or anxiety states was observed between the 5-HT7 receptor knockout mice and wild type controls. However, in the Porsolt swim test, 5-HT7 receptor knockout mice showed a significant decrease in immobility compared to controls, a phenotype similar to antidepressant treated mice. Intriguingly, treatment of wild types with SB-258719, a selective 5-HT7 receptor antagonist, did not produce a significant decrease in immobility unless animals were tested in the dark (or active) cycle, rather than the light, adding to the body of evidence suggesting a circadian influence on receptor function. Extracellular recordings from hypothalamic slices showed that circadian rhythm phase shifts to 8-OH-DPAT are attenuated in the 5-HT7 receptor KO mice also indicating a role for the receptor in the regulation of circadian rhythms. These pharmacological and genetic knockout studies provide the first direct evidence that 5-HT7 receptor antagonists should be investigated for efficacy in the treatment of depression.

An orally active, water-soluble neurokinin-1 receptor antagonist suitable for both intravenous and oral clinical administration.

1-(5-[[(2R,3S)-2-([(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholin-4-yl]methyl]-2H-1,2,3-triazol-4-yl)-N,N-dimethylmethanamine hydrochloride 3 is a high affinity, orally active, h-NK(1) receptor antagonist with a long central duration of action and a solubility in water of >100 mg/mL. The construction of the 5-dimethylaminomethyl 1,2,3-triazol-4-yl unit, which incorporates the solubilizing group of 3, was accomplished by thermal rearrangement of a propargylic azide in the presence of dimethylamine. Compound 3 is highly effective in pre-clinical tests that are relevant to clinical efficacy in emesis and depression.

4,4-Disubstituted piperidine high-affinity NK1 antagonists: structure-activity relationships and in vivo activity.

Previously reported studies from these laboratories described the design of a novel series of high-affinity NK1 antagonists based on the 4,4-disubstituted piperidine ring system. Further structure-activity studies have now established that for high NK1 affinity the benzyl ether side chain must be 3,5-disubstituted and highly lipophilic, the optimal side chain being the 3, 5-bis(trifluoromethyl)benzyl ether, 12 (hNK1 IC50 = 0.95 nM). Additional studies have shown that this class of NK1 antagonist tolerates a wider range of substituents on the piperidine nitrogen, including acyl (38) (hNK1 IC50 = 5.3 nM) and sulfonyl (39) (hNK1 IC50 = 5.7 nM) derivatives. Following preliminary pharmacokinetic analysis, two compounds (32 and 43) were selected for in vivo study in the resiniferotoxin-induced vascular leakage model, both showing excellent profiles (ID50 = 0.22 and 0.28 mg/kg, respectively).

High affinity phenylglycinol-based NK1 receptor antagonists.

Heterocyclic replacements for the carboxamido group of the previously disclosed phenylglycinol-based human NK1 (hNK1) receptor antagonists have been investigated, ultimately leading to acyclic compounds with sub-nanomolar affinity for the hNK1 receptor.

Identification of a series of 3-(benzyloxy)-1-azabicyclo[2.2.2]octane human NK1 antagonists.

The synthesis and in vitro and in vivo evaluation of a series of 3-(benzyloxy)-1-azabicyclo-[2.2.2]octane NK1 antagonists are described. While a number of 3,5-disubstituted benzyl ethers afford high affinity, the 3,5-bis(trifluoromethyl)benzyl was found to combine high in vitro affinity with good oral activity. Detailed structure-activity relationship studies in conjunction with data from molecular modeling and mutagenesis work have allowed the construction of a model of the pharmacophore. Specific interactions that have been identified include an interaction between His-197 and one of the rings of the benzhydryl, a lipophilic pocket containing His-265 that the benzyl ether occupies, and a possible hydrogen bond between Gln-165 and the oxygen of the benzyl ether.

Identification of L-tryptophan derivatives with potent and selective antagonist activity at the NK1 receptor.

As part of a program of screening the Merck sample collection, N-ethyl-L-tryptophan benzyl ester was identified as a weak antagonist at the substance P (NK1) receptor. Structure-activity studies showed that the indole ring system could be replaced by 3,4-dichlorophenyl, alpha- or beta-naphthyl, or benzthiophene with retention or only small loss of affinity. It was found that acylation of the tryptophan nitrogen gave compounds with higher affinity than N-ethyl or other basic amines. Optimization of substitution on the benzyl ester led to the identification of the 3,5-bis-(trifluoromethyl)benzyl ester of N-acetyl-L-tryptophan 26 as a potent and selective substance P receptor antagonist. Compound 26 blocked substance P induced dermal extravasation in vivo and was the most potent compound from this structurally novel class of antagonists which further adds to the diversity of small molecules that bind to the (NK1) receptor.

A pitfall in the diagnosis of lobar collapse.

In patients who have a superior accessory fissure, collapse of the upper or middle lobe may be overlooked as the anomalous fissure may be mistaken for the horizontal fissure on the postero-anterior view. Five cases are presented.

Simplified peripheral arteriography.

Demonstration of both iliofemoral arteries and their peripheral run-off is usually performed either by the translumbar approach, or by placing a pigtail catheter at the aortic bifurcation. A modified version of the old retrograde pressure method, simply using a cannula in one femoral artery, is described. There was considerable saving in materials, personnel and time. This method may once again be the method of choice in a busy radiology department.

The PRRB lives on as an appeal mechanism for healthcare providers.

Despite popular belief, the PRRB is still an important means of appeal for healthcare providers--especially hospitals, nursing homes, and home care agencies. The PRRB, a result of the 1972 Medicare amendments, was originally created as an appeals route for providers under cost-based reimbursement. Although new approaches for payment of healthcare services are being developed, none related to cost-based reimbursement, inpatient hospital costs is still the only category where the payment mechanism has been changed. Hence, the PRRB can still be an important avenue of appeal.

Sonography as an aid to diagnosis of caecal carcinoma in the elderly.

Many elderly patients with suspected colonic neoplasm are referred to radiology departments for barium enema. Despite routine use of laxatives and colonic washouts and employment of antispasmodic drugs, problems occur with faecal residue and poor retention of barium. This may lead to inadequate demonstration of the caecum. Over a 6-month period sonography following the barium enema allowed a confident diagnosis of a caecal mass lesion to be made in five such patients, whose barium enema had been suspicious but suboptimal. It is suggested that in some patients sonography, where positive, may shorten and facilitate investigation.

Ultrasound guided percutaneous abdominal abscess drainage.

Traditional management of abdominal abscess is according to classical surgical methods. Catheter or needle drainage of these abscesses, using ultrasound both as an imaging modality and as a monitor of technique, offers a safe and rapid method of drainage of all types of abdominal abscess and eliminates surgery in many patients. Eleven abdominal and retroperitoneal abscesses were satisfactorily drained under ultrasound control in ten patients. No abscess recurred, but in three patients subsequent surgery was performed, in one because the abscess was multiloculated, and in the other two to exclude underlying malignancy.

Hypernephroma embolisation--is it worthwhile?

Transcatheter embolisation was performed in 16 patients with hypernephroma, using either Oxycel, Gelfoam, or steel wire coil(s). Thirteen patients proceeded to early nephrectomy. Surgery was facilitated in four patients with large hypervascular tumours, three of whom had vena caval occlusion. Patients with small, or only moderately vascular tumours, did not benefit from the technique as assessed at nephrectomy. The technique was used as a palliative procedure in three patients, haematuria stopped in two, and abolition of high-output heart failure was achieved in one. Owing to the danger of this technique, it is suggested that its use be restricted to (a) rendering patients with large hypervascular tumours more suitable for surgery, and (b) in palliation of inoperable patients who have symptoms such as severe haematuria. The effect of the technique on survival time remains uncertain.