H3 receptor blockade by thioperamide enhances cognition in rats without inducing locomotor sensitization.

Rationale: Attention deficit hyperactivity disorder (ADHD) is currently treated with psychomotor stimulants, including methylphenidate and amphetamine. Several adverse effects are associated with these drugs, however, such as agitation and abuse. H(3) receptor antagonists are under clinical investigation for ADHD.

Molecular modeling and pharmacological analysis of species-related histamine H(3) receptor heterogeneity.

Presynaptic histamine H(3) receptors (H(3)R) regulate neurotransmitter release in the central nervous system, suggesting an important role for H(3) ligands in human diseases such as cognitive disorders, sleep disturbances, epilepsy, or obesity. Drug development for many of these human diseases relies upon rodent-based models. Although there is significant sequence homology between the human and rat H(3)Rs, some compounds show distinct affinity profiles.

Differential activation of dual signaling responses by human H1 and H2 histamine receptors.

Stimulation of human H1 and H2-histamine receptors (HRs) primarily activates signaling pathways to increase intracellular calcium [Ca2+]i and cyclic AMP (cAMP), respectively. Activation of H2-HR in human embryonic kidney (HEK) cells by histamine and dimaprit increases both cAMP formation and [Ca2+]i, as determined by cAMP-scintillation proximity assays and fluorescence imaging plate reader (FLIPR) assays. In HEK cells expressing relatively high levels of H2-HR (Bmax=26 pmol/mg protein), histamine and dimaprit are full agonists in eliciting cAMP responses with pEC50 values of 9.

Synthesis and SAR of aminoalkoxy-biaryl-4-carboxamides: novel and selective histamine H3 receptor antagonists.

Novel 4'-[(NR1R2-1-yl)]-propoxy-biaryl-4-carboxamides were designed and synthesized. All compounds were tested for affinity at histamine H(3)receptors. Most compounds were highly potent and selective for human and rat H(3) receptors and selected examples such as A-349821 showed functional antagonism of H(3) receptors in vitro and in a mouse dipsogenia model.

Two novel and selective nonimidazole histamine H3 receptor antagonists A-304121 and A-317920: I. In vitro pharmacological effects.

Histamine H3 receptor (H3R) antagonists enhance neurotransmitter release and are being developed for the treatment of a variety of neurological and cognitive disorders. Many potent histamine H3R antagonists contain an imidazole moiety that limits receptor selectivity and the tolerability of this class of compounds. Here we present the in vitro pharmacological data for two novel piperazine amide ligands, A-304121 [4-(3-((2R)-2-aminopropanoyl-1-piperazinyl)propoxy)phenyl)cyclopropylmethanone] and A-317920 [N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxo-ethyl-)-2-furamide], and compare them with the imidazole H3R antagonists ciproxifan, clobenpropit, and thioperamide.

Two novel and selective nonimidazole H3 receptor antagonists A-304121 and A-317920: II. In vivo behavioral and neurophysiological characterization.

Pharmacological blockade of central histamine H3 receptors (H3Rs) enhances cognition in rodents and offers promise for the clinical treatment of neurological disorders. However, many previously characterized H3R antagonists are either not selective for H3Rs or have potentially significant tolerability issues. Here, we present in vivo behavioral and neurophysiological data for two novel and selective H3R antagonists with improved safety indices.

Microparticle column geometry in acoustic stationary fields.

Particles suspended in a fluid will experience forces from stationary acoustic fields. The magnitude of the force depends on the time-averaged energy density of the field and the material properties of the particles and fluid. Forces acting on known particles smaller than 20 microm were studied.

Gains in sensitivity with a device that mixes microarray hybridization solution in a 25-microm-thick chamber.

A microarray hybridization system that allows mixing in volumes comparable to those used by glass coverslips is presented. This system is composed of a disposable flexible lid that binds to 1 in. x 3 in.

Aminoalkoxybiphenylnitriles as histamine-3 receptor ligands.

Biaryl nitrile amines were prepared and found to have high affinity and selectivity for human and rat histamine H(3) receptors.

Synthesis and evaluation of potent pyrrolidine H(3) antagonists.

The synthesis and biological evaluation of novel antagonists of the rat H(3) receptor are described. These compounds differ from prototypical H(3) antagonists in that they do not contain an imidazole moiety, but rather a substituted aminopyrrolidine moiety. A systematic modification of the substituents on the aminopyrrolidine ring was performed using pre-formatted precursor sets, where applicable, to afford several compounds with high affinity and selectivity for the H(3) receptor.

Differential in vivo effects of H3 receptor ligands in a new mouse dipsogenia model.

The selective H(3) receptor agonist (R)-alpha-methylhistamine [(R)-alpha-MeHA] stimulates drinking in the adult rat. In the present study, we investigated the role of the H(3) receptor in mediating this behavior in a new dipsogenia model using the CD-1 mouse. In addition, the putative inverse agonists ciproxifan, thioperamide and clobenpropit; the reported antagonist (1R,2R)-4-[2-(5,5-dimethylhex-1-ynyl)cyclopropyl]imidazole (GT-2331); and the putative neutral antagonist/weak partial agonist proxyfan were evaluated for possible differences in pharmacological activity in this new model.

Structure-activity relationships of non-imidazole H(3) receptor ligands. Part 2: binding preference for D-amino acids motifs.

Structure-activity relationship studies on novel non-imidazole, D-amino acid containing ligands of histamine 3 receptors are presented. A-304121 is a D-alanine piperazine amide with high affinity at the rat H(3) receptor.

Structure-activity relationships of non-imidazole H(3) receptor ligands. Part 1.

SAR studies for novel non-imidazole containing H(3) receptor antagonists with high potency and selectivity for rat H(3) receptors are described. A high throughput screening lead, A-923, was further elaborated in a systematic manner to clarify a pharmacophore for this class of aryloxyalkyl piperazine based compounds.

Effects of histamine H(3) receptor ligands GT-2331 and ciproxifan in a repeated acquisition avoidance response in the spontaneously hypertensive rat pup.

Histamine H(3) receptor antagonists have been proposed as potentially useful therapeutic agents for the treatment of several disorders including attention deficit, schizophrenia, depression, and Alzheimer's disease. We have developed a repeated acquisition version of an inhibitory avoidance task using spontaneously hypertensive rat (SHR) pups that we believe provides a reproducible measure of the cognitive and attention deficits often characteristic of these disease states, and evaluated two H(3) receptor antagonists. Male SHR, Wistar (WI) and Wistar Kyoto (WKY) rat pups (20--24 days old) were trained to avoid a mild footshock (0.

Modeling of relationships between pharmacokinetics and blockade of agonist-induced elevation of intraurethral pressure and mean arterial pressure in conscious dogs treated with alpha(1)-adrenoceptor antagonists.

Fiduxosin is a new alpha(1)-adrenoceptor antagonist targeted for the treatment of symptomatic benign prostatic hyperplasia. The purpose of this study was to determine and compare the potencies of the alpha(1)-adrenoceptor antagonists terazosin, doxazosin, tamsulosin, and fiduxosin, based on relationships between plasma drug concentrations and blockade of phenylephrine (PE)-induced intraurethral (IUP) and mean arterial pressure (MAP) responses after single oral dosing in conscious male beagle dogs. Magnitude of blockade and plasma concentrations were evaluated at selected time points over 24 h.

Effect of fiduxosin, an antagonist selective for alpha(1A)- and alpha(1D)-adrenoceptors, on intraurethral and arterial pressure responses in conscious dogs.

Fiduxosin is an alpha(1)-adrenoceptor antagonist with higher affinity for alpha(1A)-adrenoceptors and for alpha(1D)-adrenoceptors than for alpha(1B)-adrenoceptors. Our hypothesis is that such a compound with higher affinity for subtypes implicated in the control of lower urinary tract function and lower affinity for a subtype implicated in the control of arterial pressure could result in a superior clinical profile for the treatment of lower urinary tract symptoms suggestive of benign prostatic obstruction. The purpose of this study was to evaluate the potency and selectivity of fiduxosin for effects on prostatic intraurethral pressure (IUP) versus mean arterial pressure (MAP) relative to current clinical standards, terazosin and tamsulosin, in conscious dogs.

Preclinical pharmacology of fiduxosin, a novel alpha(1)-adrenoceptor antagonist with uroselective properties.

Benign prostatic hyperplasia (BPH), common in aging males, is often treated with alpha(1)-adrenoceptor antagonists. To minimize hypotensive and other side effects, compounds with selective antagonist activity at alpha(1A)- and alpha(1D)- (compared with alpha(1B)-) adrenoceptors were evaluated that would block lower urinary tract alpha(1)-adrenoceptors in preference to cardiovascular alpha(1B)-adrenoceptors. Fiduxosin (3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl]-8-phenyl-pyrazino[2',3':4,5] thieno-[3,2-d]pyrimidine-2,4(1H,3H)-dione; ABT-980) was tested in radioligand binding assays, isolated tissue bioassays, intraurethral pressure (IUP) tests in isoflurane-anesthetized dogs, and blood pressure analyses in spontaneously hypertensive rats (SHR).

Species-related pharmacological heterogeneity of histamine H(3) receptors.

We compared radioligand binding and functional data for histamine H(3) receptor ligands across different tissues or species to evaluate the basis for pharmacological evidence of receptor heterogeneity previously reported. Agonist binding affinities showed correlation coefficients near unity in comparing human, dog, rat, and guinea pig cerebral cortical histamine H(3) receptors. Antagonist binding affinities revealed lower correlations for human compared to dog, rat, or guinea pig, suggesting species-based pharmacological differences.

Comparison of alpha 1-adrenoceptor agonists in canine urethral pressure profilometry and abdominal leak point pressure models.

Purpose: We describe and compare the usefulness of 3 minimally invasive dog urethral function models to demonstrate the efficacy potential of alpha 1 agonists for stress urinary incontinence. From this overall composite dataset the efficacy profiles of the alpha 1A selective agonist A-61603 and the active metabolite of midodrine ST-1059 were specifically compared.

Materials And Methods: Isoflurane anesthetized multiparous female beagle dogs were used in all studies.

Induction of disseminated Mycobacterium avium in simian AIDS is dependent upon simian immunodeficiency virus strain and defective granuloma formation.

Mycobacterium avium complex (MAC) is the most common disseminated bacterial disease in patients infected by the human immunodeficiency virus. Although murine models of disseminated MAC exist, they are primarily based on underlying genetic susceptibilities and cannot adequately address the complex interactions that occur between host, mycobacteria, and immunosuppressive lentivirus. To address this problem we have developed an experimental system to co-inoculate rhesus macaques with the simian immunodeficiency virus (SIV) and a clinical M.

Structure-activity studies for a novel series of bicyclic substituted hexahydrobenz[e]isoindole alpha1A adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia.

In search of a uroselective alpha1A subtype selective antagonist, a novel series of 6-OMe hexahydrobenz[e]isoindoles attached to a bicyclic heterocyclic moiety via a two-carbon linker was synthesized. It was found that in contrast to the previously described series of tricyclic heterocycles,(1) this bicyclic series has very specific requirements for the heterocyclic attachments. The most important structural features contributing to the alpha1A/alpha1B selectivity of these compounds were identified.

6,6'-Bis(2-hydroxyphenyl)-2,2'-bipyridine manganese(III) complexes: a novel series of superoxide dismutase and catalase mimetics.

A series of novel manganese(III) complexes is described based on a 6,6'-bis(2-hydroxyphenyl)-2,2'-bipyridine template. These complexes show superoxide dismutase and catalase activity. The effect of the aromatic substitution pattern on the SAR is described.

Two novel and potent 3-[(o-methoxyphenyl)piperazinylethyl]-5-phenylthien.

The synthesis and in vitro characterization of A-119637 and A-123189, two novel, selective and potent alpha1D antagonists, are described.