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Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) regulates the proliferation and differentiation of neuronal progenitor cells during brain development. Consequently, DYRK1A has attracted interest as a target for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD) and Down's syndrome. Recently, the inhibition of DYRK1A has been investigated as a potential treatment for diabetes, while DYRK1A's role as a mediator in the cell cycle has garnered interest in oncologic indications. Structure-activity relationship (SAR) analysis in combination with high-resolution X-ray crystallography leads to a series of pyrazolo[1,5- b ]pyridazine inhibitors with excellent ligand efficiencies, good physicochemical properties, and a high degree of selectivity over the kinome. Compound 11 exhibited good permeability and cellular activity without P-glycoprotein liability, extending the utility of 11 in an in vivo setting. These pyrazolo[1,5- b ]pyridazines are a viable lead series in the discovery of new therapies for the treatment of diseases linked to DYRK1A function.

Catalytic oxidative cyclisation reactions have been employed for the synthesis of the E and F rings of the complex natural product target pectenotoxin 4. The choice of metal catalyst (cobalt- or osmium-based) allowed for the formation of THF rings with either trans or cis stereoselectivity. Fragment union using a modified Julia reaction then enabled the synthesis of an advanced synthetic intermediate containing the EF and G rings of the target., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A new strategy that employs an exocyclic stereocenter to effect diastereocontrol in the tethered aminohydroxylation (TA) reaction is applied to the stereoselective synthesis of a range of amino alcohols in good to excellent yields, and with anti selectivities of up to 20:1. The influence of the reaction conditions and substrate parameters on the level of diastereocontrol is described. Furthermore, an "inside alkoxy" model is employed to rationalize the sense and degree of stereoselectivity observed in these systems., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A backup molecule to compound 2 was sought by targeting the most likely metabolically vulnerable site in this molecule. Compound 18 was subsequently identified as a potent P2X(7) antagonist with very low in vivo clearance and high oral bioavailability in all species examined. Some evidence to support the role of P2X(7) in the etiology of pain is also presented., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

A novel osmium-catalysed oxidative cyclisation of 1,2-diols bearing a pendant vinyl silane affords THFs that contain silicon functionality at the ring junction. When the cyclisation occurs onto a vinyl benzyldimethylsilyl group, the resulting silyl group can act as a masked hydroxyl group and undergo a Fleming-Tamao type oxidation at a later stage to form the corresponding lactol. The scope of this reaction can also be extended beyond 1,2-diols and applied to the cyclisation of α-hydroxy-sulfonamides and α-hydroxy-amides.

A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X(7) receptor antagonist. Structure-activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X(7) antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies., (Copyright 2010 Elsevier Ltd. All rights reserved.)

A series of analogues of the pyrazole lead 1 were synthesized in which the heterocyclic core was replaced with an imidazole. A number of potent antagonists were identified and structure-activity relationships (SAR) were investigated both with respect to activity at the P2X(7) receptor and in vitro metabolic stability. Compound 10 was identified as a potent P2X(7) antagonist with reduced in vitro metabolism and high solubility., (2010 Elsevier Ltd. All rights reserved.)

Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. Herein, is described a series of potent inhibitors based on an hydroxyethylamine (HEA) transition state mimetic template. These inhibitors interact with the non prime side of the enzyme using a novel edge-to-face interaction with Arg-296., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Structure-activity relationships (SAR) of analogues of lead compound 1 were investigated and compound 16 was selected for further study in animal models of pain. Compound 16 was shown to be a potent antihyperalgesic agent in both the rat acute complete Freund's adjuvant (CFA) model of inflammatory pain [Iadarola, M. J.; Douglass, J.; Civelli, O.; Naranjo, J. R. rain Res.1988, 455, 205] and the knee joint model of chronic inflammatory pain [Wilson, A. W.; Medhurst, S. J.; Dixon, C. I.; Bontoft, N. C.; Winyard, L. A.; Brackenborough, K. T.; De Alba, J.; Clarke, C. J.; Gunthorpe, M. J.; Hicks, G. A.; Bountra, C.; McQueen, D. S.; Chessell, I. P. Eur. J. Pain2006, 10, 537]., (Copyright 2010 Elsevier Ltd. All rights reserved.)

High-throughput screening identified compound 1 as a potent P2X(7) receptor antagonist suitable for lead optimisation. Structure-activity relationships (SAR) of a series of (1H-pyrazol-4-yl)acetamides were investigated and compound 32 was identified as a potent P2X(7) antagonist with enhanced potency and favourable physicochemical and pharmacokinetic properties., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Replacing trifluoroacetic acid with a catalytic amount of Lewis acid in the osmium mediated oxidative cyclization results in higher yielding reactions that can proceed nearly an order of magnitude faster. The osmium loading can also be reduced to as little as 0.2 mol %. Furthermore, these mildly acidic conditions are capable of tolerating a wide range of acid sensitive protecting groups that are incompatible with previous cyclization conditions.

Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. We have recently disclosed a series of transition-state mimetic BACE-1 inhibitors showing nanomolar potency in cell-based assays. Amongst them, GSK188909 (compound 2) had favorable pharmacokinetics and was the first orally bioavailable inhibitor reported to demonstrate brain amyloid lowering in an animal model. In this Letter, we describe the reasons that led us to favor a second generation of inhibitors for further in vivo studies.

Our first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as a key target for Alzheimer's disease by demonstrating amyloid lowering in an animal model, albeit at rather high doses. Finding a molecule from this series which was active at lower oral doses proved elusive and demonstrated the need to find a novel series of inhibitors with improved pharmacokinetics. This Letter describes the discovery of such inhibitors.

Our first generation of hydroxyethylamine BACE-1 inhibitors proved unlikely to provide molecules that would lower amyloid in an animal model at low oral doses. This observation led us to the discovery of a second generation of inhibitors having nanomolar activity in a cell-based assay and with the potential for improved pharmacokinetic profiles. In this Letter, we describe our successful strategy for the optimization of oral bioavailability and also give insights into the design of compounds with the potential for improved brain penetration.

Background and Purpose: AZ11645373 and N-{2-methyl-5-[(1R, 5S)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylcarbonyl]phenyl}-2-tricyclo[3.3.1.13,7]dec-1-ylacetamide hydrochloride (compound-22) are recently described P2X(7) receptor antagonists. In this study we have further characterized these compounds to determine their mechanism of action and interaction with other species orthologues., Experimental Approach: Antagonist effects at recombinant and chimeric P2X(7) receptors were assessed by ethidium accumulation and radioligand-binding studies., Key Results: AZ11645373 and compound-22 were confirmed as selective non-competitive antagonists of human or rat P2X(7) receptors respectively. Both compounds were weak antagonists of the mouse and guinea-pig P2X(7) receptors and, for each compound, their potency estimates at human and dog P2X(7) receptors were similar. The potency of compound-22 was moderately temperature-dependent while that of AZ11645373 was not. The antagonist effects of both compounds were slowly reversible and were not prevented by decavanadate, suggesting that they were allosteric antagonists. Indeed, the compounds competed for binding sites labelled by an allosteric radio-labelled P2X(7) receptor antagonist. The species selectivity of AZ11645373, but not compound-22, was influenced by the nature of the amino acid at position 95 of the P2X(7) receptor. N(2)-(3,4-difluorophenyl)-N(1)-[2-methyl-5-(1-piperazinylmethyl)phenyl]glycinamide dihydrochloride, a positive allosteric modulator of the rat receptor, reduced the potency of compound-22 at the rat receptor but had little effect on the actions of AZ11645373., Conclusions: AZ11645373 and compound-22 are allosteric antagonists of human and rat P2X(7) receptors respectively. The differential interaction of the two compounds with the receptor suggests there may be more than one allosteric regulatory site on the P2X(7) receptor at which antagonists can bind and affect receptor function.

BACE-1 inhibition has the potential to provide a disease-modifying therapy for the treatment of Alzheimer's disease. Optimization of a first generation of BACE-1 inhibitors led to the discovery of novel hydroxyethylamines (HEAs) bearing a tricyclic nonprime side. These derivatives have nanomolar cell potency and are orally bioavailable.

This paper describes the discovery of non-peptidic, potent, and selective hydroxy ethylamine (HEA) inhibitors of BACE-1 by replacement of the prime side of a lead di-amide 2. Inhibitors with nanosmolar potency and high selectivity were identified. Depending on the nature of the P(1)(') and P(2)(') substituents, two different binding modes were observed in X-ray co-crystal structures.

This article is focusing on further optimization of previously described hydroxy ethylamine (HEA) BACE-1 inhibitors obtained from a focused library with the support of X-ray crystallography. Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays.

Background and Purpose: Antagonist effects at the P2X(7) receptor are complex with many behaving in a non-competitive manner. In this study, the effects of N-[2-({2-[(2-hydroxyethyl)amino]ethyl}amino)-5-quinolinyl]-2-tricyclo[3.3.1.1(3,7)]dec-1-ylacetamide (compound-17) and N (2)-(3,4-difluorophenyl)-N (1)-[2-methyl-5-(1-piperazinylmethyl)phenyl]glycinamide dihydrochloride (GW791343) on P2X(7) receptors were examined and their mechanism of action explored., Experimental Approach: Antagonist effects were studied by measuring agonist-stimulated ethidium accumulation in cells expressing human or rat recombinant P2X(7) receptors and in radioligand binding studies., Key Results: Compound-17 and GW791343 were non-competitive inhibitors of human P2X(7) receptors. Receptor protection studies using decavanadate and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) showed that neither compound-17 nor GW791343 competitively interacted at the ATP binding site and so were probably negative allosteric modulators of the P2X(7) receptor. GW791343 prevented the slowly reversible blockade of the human P2X(7) receptor produced by compound-17 and inhibited [(3)H]-compound-17 binding to the P2X(7) receptor suggesting they may bind to similar or interacting sites. At rat P2X(7) receptors, compound-17 was a negative allosteric modulator but the predominant effect of GW791343 was to increase agonist responses. Antagonist interaction and radioligand binding studies revealed that GW791343 did not interact at the ATP binding site but did interact with the compound-17 binding site suggesting that GW791343 is a positive allosteric modulator of the rat P2X(7) receptor., Conclusions: Compound-17 was a negative allosteric modulator of human and rat P2X(7) receptors. GW791343 was a negative allosteric modulator of the human P2X(7) receptor but at the rat P2X(7) receptor its predominant effect was positive allosteric modulation. These compounds should provide valuable tools for mechanistic studies on P2X(7) receptors.

Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. Herein, is described the lead generation effort which resulted, with the support of X-ray crystallography, in the discovery of potent inhibitors based on a hydroxy ethylamine (HEA) transition-state mimetic. These inhibitors were capable of lowering amyloid production in a cell-based assay.

Background and Purpose: The P2X(7) receptor exhibits complex pharmacological properties. In this study, binding of a [(3)H]-labelled P2X(7) receptor antagonist to human P2X(7) receptors has been examined to further understand ligand interactions with this receptor., Experimental Approach: The P2X(7) receptor antagonist, N-[2-({2-[(2-hydroxyethyl)amino]ethyl}amino)-5-quinolinyl]-2-tricyclo[3.3.1.1(3,7)]dec-1-ylacetamide (compound-17), was radiolabelled with tritium and binding studies were performed using membranes prepared from U-2 OS or HEK293 cells expressing human recombinant P2X(7) receptors., Key Results: Binding of [(3)H]-compound-17 was higher in membranes prepared from cells expressing P2X(7) receptors than from control cells and was inhibited by ATP suggesting labelled sites represented human P2X(7) receptors. Binding was reversible, saturable and modulated by P2X(7) receptor ligands (Brilliant Blue G, KN62, ATP, decavanadate). Furthermore, ATP potency was reduced in the presence of divalent cations or NaCl. Radioligand binding exhibited both positive and negative cooperativity. Positive cooperativity was evident from bell shaped Scatchard plots, reduction in radioligand dissociation rate by unlabelled compound-17 and enhancement of radioligand binding by KN62 and unlabelled compound-17. ATP and decavanadate inhibited binding in a negative cooperative manner as they enhanced radioligand dissociation., Conclusions: These data demonstrate that human P2X(7) receptors can be directly labelled and provide novel insights into receptor function. The positive cooperativity observed suggests that binding of compound-17 to one subunit in the P2X(7) receptor complex enhances subsequent binding to other P2X(7) subunits in the same complex. The negative cooperative effects of ATP suggest that ATP and compound-17 bind at separate, interacting, sites on the P2X(7) receptor.

A novel cascade reaction has been developed for the rapid construction of heterocyclic rings. The cyclization is thermally induced and does not involve the use of metal ions. This highly efficient construction of furans has been developed during studies directed toward the synthesis of the antibiotic lactonamycin 1.

[reaction: see text] Starting from readily available precursors, selenoglycosides derived from GalNAc, GlcNAc, and ManNAc were prepared by either a one- or a two-step process. The anomeric selenides underwent facile C-Se homolysis to provide the corresponding anomeric radicals, which were trapped with alkenes to give C-glycosides. This provides a general entry to alpha-C-glycosides based on 2-amino-2-deoxy sugars that is also applicable to disaccharide variants.

Tumor necrosis factor-alpha (TNF-alpha), a cytokine secreted by inflammatory cells, has been implicated in several inflammatory disease states. (E)-2(R)-[1(S)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl]-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide (Ro 32-7315), is a potent, orally active inhibitor of the TNF-alpha convertase (TACE), an enzyme responsible for proteolytic cleavage of the membrane bound precursor, pro-TNF-alpha. Ro 32-7315 inhibited a recombinant form of TACE (IC(50) = 5.2 nM) with selectivity over related matrix metalloproteinases. In a cellular assay system, THP-1 cell line, and in human and rat whole blood, Ro 32-7315 significantly reduced lipopolysaccharide (LPS)-induced TNF-alpha release with IC(50) values of 350 +/- 14 nM (n = 5), 2.4 +/- 0.5 microM (n = 5), and 110 +/- 18 nM (n = 5), respectively. Oral administration of Ro 32-7315 to Wistar rats caused a dose-dependent inhibition of LPS-induced release of systemic TNF-alpha with an ED(50) of 25 mg/kg. Treatment (days 0-14) of Allen and Hamburys hooded rats with Ro 32-7315 (2.5, 5, 10, and 20 mg/kg, i.p., twice daily) significantly reduced adjuvant-induced secondary paw swelling (42, 71, 83, and 93%, respectively) as compared with the vehicle group. In the Ro 32-7315-treated group, the reduced paw swelling was associated with improved lesion score and joint mobility. Furthermore, in a placebo-controlled, single-dose study, Ro 32-7315 given orally (450 mg) significantly suppressed ex vivo, LPS-induced TNF-alpha release in the whole-blood samples taken from healthy male and female volunteers (mean inhibition of 42% over a 4-h duration, n = 6). These data collectively support the potential use of such a compound for the oral treatment of inflammatory disorders.

[structure] C-Glycosides of N-acyl 2-amino-2-deoxygalactose (acyl = MeCO, CF(3)CO, t-BuOCO) are available in a stereoselective manner by trapping of an anomeric radical with an activated alkene. Using anomeric selenides, radical generation and trapping is carried out under conditions that avoid competitive reduction, and this chemistry has been applied to the synthesis of the novel C-glycoside analogue of O-benzyl alpha-D-GalNAc.

The synthesis of the Fmoc-protected C-glycosyl tyrosines 1 and 2, together with two other related C-glycosyl tyrosines, has been achieved. Key reactions involved (i) the reaction of a glycal with an organozinc reagent (carrying an aryl iodide function) in the presence of a Lewis acid to establish the C-glycosyl linkage and (ii) subsequent cross coupling of the aryl iodide to an alanyl zinc reagent (in the presence of a Pd(0) catalyst) to complete the construction of the alpha-amino acid moiety. Using solid-phase peptide synthesis methods, two units of the mannosyl derivative 1 (shown as L-Tyr[C-Ac(4)-alpha-D-Man]) have been incorporated (with four units of glycine) into the linear hexapeptide 3 which was then converted to the C(2)-symmetric cyclic oligopeptide 4.

An investigation has been made of the effects of the selective alpha 2-adrenoceptor antagonist, idazoxan, on the plasma immunoreactive insulin and glucose responses following a glucose stimulus in conscious euglycaemic rats. UK 14304 (100 micrograms/kg), a selective alpha 2-adrenoceptor agonist, reduced the insulin response and potentiated the hyperglycaemia elicited by an intra-arterial glucose load (0.25 g/kg), thereby confirming previous findings that alpha 2-adrenoceptors can influence pancreatic insulin secretion and glycaemia. The effects of UK 14304 were totally abolished by idazoxan (1.0 mg/kg), indicating that idazoxan, at the dose studied, effectively antagonized alpha 2-adrenoceptor-mediated responses. However, idazoxan (1.0 mg/kg) by itself did not significantly affect the plasma glucose and insulin responses to glucose challenge. The data indicate that selective alpha 2-adrenoceptor blockade per se does not potentiate glucose-evoked insulin secretion.

1. The role of alpha- and beta-adrenoceptor subtypes in the regulation of plasma glucose and immunoreactive insulin (IRI) levels has been investigated in normal conscious fasted rats by employing selective agonists and antagonists. 2. Adrenaline (0.2 mg kg-1)-induced hyperglycaemia was abolished by the selective alpha 2-adrenoceptor antagonist idazoxan (1.0 mg kg-1), unaltered by non-selective beta-adrenoceptor blockade (propranolol, 1.0 mg kg-1) and potentiated by the selective alpha 1-adrenoceptor antagonist prazosin (0.3 mg kg-1). Adrenaline increased plasma IRI levels in the presence of idazoxan but not in the presence of either prazosin or propranolol. 3. The selective alpha 2-adrenoceptor agonists UK 14304 (0.1 and 0.3 mg kg-1) and BHT-920 (0.2 and 0.5 mg kg-1) elicited dose-dependent hyperglycaemic responses, but did not alter plasma IRI levels. UK 14304 (0.1 mg kg-1)-evoked hyperglycaemia was blocked by idazoxan but not by prazosin. 4. The selective alpha 1-adrenoceptor agonists methoxamine (0.3 mg kg-1) and phenylephrine (0.3 mg kg-1) failed to modify either plasma glucose or IRI levels. 5. Isoprenaline (0.2 mg kg-1) elicited hyperglycaemic and insulinotropic responses which were attenuated by propranolol (1.0 mg kg-1) and the selective beta 2-adrenoceptor antagonist ICI 118551 (1.0 mg kg-1), but not by the beta 1-selective antagonists atenolol (1.0 mg kg-1) and betaxolol (1.0 mg kg-1). 6. None of the antagonists per se affected basal plasma glucose or IRI concentrations, except prazosin (1.0 mg kg-1). 7. The results indicate that adrenoceptors do not appear to be involved in regulating basal plasma glucose and IRI concentrations in the fasted rat. However, the effects of catecholamines on these parameters are mediated by alpha 2- and beta 2-adrenoceptors, whereas alpha,- or beta l-adrenoceptors do not appear to be involved.

Four 2-alkyl (methyl, ethyl, n-propyl and isopropenyl) analogues of idazoxan (RX 781094) have been synthesized and assessed in terms of their central alpha 2/alpha 1-adrenoceptor selectivity and alpha 2-adrenoceptor antagonist potency using both in vitro and in vivo tests in the rat. In cortical binding assays using [3H]-idazoxan and [3H]-prazosin, idazoxan had a 5 times greater alpha 2/alpha 1-selectivity than yohimbine. The 2-alkyl substituted analogues all showed improved selectivity, being between 17 and 29 times more selective than yohimbine for [3H]-idazoxan binding sites. In terms of central antagonist potency in vivo, the most favourable substitutions were 2-ethyl (RX 811033) and 2-n-propyl (RX 811054). Compared with yohimbine, these analogues were, respectively, 36 and 18 times more potent intravenously and 5 and 7.5 times more potent orally in their antagonism of guanoxabenz-induced mydriasis in the pentobarbitone-anaesthetized rat. All the analogues had a duration of action similar to that of idazoxan, which was significantly shorter than that of yohimbine. The results indicate that introduction of alkyl groups in the 2-position of idazoxan greatly increases the alpha 2/alpha 1-adrenoceptor selectivity as measured in binding studies. Improved alpha 2-adrenoceptor affinity and antagonist potency were particularly associated with the 2-ethyl and 2-n-propyl analogues.

Experiments have been performed to assess the potency of idazoxan (RX 781094) at alpha and beta-adrenoceptors and dopamine receptors and on catecholamine uptake processes in rat brain. The effects of idazoxan on the turnover rates of noradrenaline and dopamine have been determined. Radioligand binding studies with cerebral cortex membranes have demonstrated that idazoxan exhibits 46-fold selectivity for alpha 2-adrenoceptors labelled by (3H)-idazoxan (Mean Ki +/- S.E.M. = 3.1 +/- 0.4 nM) compared with alpha 1-adrenoceptors labelled by (3H)-prazosin (Mean Ki +/- S.E.M. = 142 +/- 27 nM). Under the same conditions, yohimbine showed 6-fold selectivity for alpha 2-adrenoceptors. Idazoxan had low affinity for beta-adrenoceptors labelled by (3H)-dihydroalprenolol (IC50 value greater than 10 microM), for dopamine receptors labelled by (3H)-domperidone (IC50 value greater than 20 microM), for the (3H)-noradrenaline uptake site in rat hypothalamus (IC50 = 31 microM) and for the (3H)-dopamine uptake site in rat striatum (IC50 value approximately 800 microM). In rats treated with alpha-methyl-p-tyrosine, idazoxan (10-80 mg/kg, po) produced a marked increase (63% at 10, 217% at 20 mg/kg, po) in the apparent rate of turnover of noradrenaline in rat cortex/striatum, without affecting the rate of turnover of dopamine. This was in contrast to yohimbine (5-20 mg/kg, po) which increased the turnover rates of both catecholamines. In the absence of alpha-methyl-p-tyrosine, idazoxan (5-40 mg/kg, po) produced a dose related increase in the MHPG concentration and a small (20-30%) reduction in the steady state concentration of NA; the duration of the reduction was dose-related. DA steady state concentrations were unaffected. Idazoxan is a new selective alpha 2-adrenoceptor antagonist which should prove a valuable investigative tool in neurochemical studies and which may be a useful clinical agent in the management of the affective disorders.

This paper describes the synthesis and pharmacological evaluation of a number evaluation of a number of substituted 1,3,4-thiadiazoles. The first member of the series, 2-(aminomethyl)-5-(2-biphenylyl)-1,3,4-thiadiazole (7) was found to possess potent anticonvulsant properties in rats and mice and compared favorably with the standard anticonvulsant drugs phenytoin, phenobarbital, and carbamazepine in a number of test situations. The potency of compound 7 was maintained on alkylation of the side-chain nitrogen atom; however, aryl substitution or chain lengthening caused a drop in potency. Replacement of the 2-biphenylyl group by phenyl or benzyl also lead to inactive compounds.

The synthesis and anticonvulsant activity of a series of 2-aryl-5-hydrazino-1,3,4-thiadiazoles are described. The combination of preferred aromatic substituents in the 2-position coupled with alkyl substitution on the hydrazine moiety led to a number of potent compounds lacking sedation, ataxia, or lethality. 5-(2-Biphenylyl)-2-(1-methylhydrazino)-1,3,4-thiadiazole (4m) represents a new class of anticonvulsant agent and compares favorably with the standard drugs phenytoin, phenobarbital, and carbamazepine.

A radioreceptor assay to determine the plasma concentration of idazoxan, a potent, highly selective antagonist for the alpha(2)-adrenoreceptor, is described. The assay is based upon a technique in which plasma extracts containing idazoxan compete with radiolabelled ligand for binding sites on receptor-rich tissue prepared from beef brain cortex. Using a logistic data-fit the limit of detection is of the order of 1 ng ml(-1) and represents a 10-fold increase in sensitivity over that from an established HPLC procedure. Comparison of human plasma data from the two assays indicates a correlation coefficient of 0.92 (N = 27) although the chromatographic method gave consistently higher values than the binding assay. The binding assay requires no sample extraction or pretreatment of plasma and its accuracy, precision and inherent specificity are such that the method represents a useful alternative to HPLC for therapeutic drug monitoring.

The synthesis and anticonvulsant activity of a number of 2-aryl-5-guanidino-1,3,4 thiadiazoles are described. The unsubstituted guanidine 2a was found to possess potent anticonvulsant properties; considerable reduction or loss of activity however was observed with the majority of the substituted guanidines. Incorporation of the guanidine group into an imidazoline ring also resulted in a loss of activity. Secondary pharmacological evaluation confirmed the anticonvulsant properties of 2a but also revealed that the compound exhibited a considerable degree of sedative activity.

Two different structural types of 2-aryl-1,3,4-thiadiazole amidines were synthesized and evaluated for anticonvulsant activity. Enhancement of the inherent anticonvulsant activity therein and separation of this activity from the accompanying sedative action of these compounds were attempted. The most potent compounds occurred in the 2-(trifluoromethyl)phenyl series of type 3 amidines, but they also possessed a relatively high level of neurotoxicity and sedation as demonstrated in the rotorod test.