Optimization of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene)acetamide derivatives as arginine vasopressin V2 receptor agonists and discussion of their binding modes.

A series of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene)acetamide derivatives were optimized to achieve potent agonistic activity, both in vitro and in vivo, for the arginine vasopressin V(2) receptor, resulting in the eventual discovery of compound 1g. Molecular modeling of compound 1g with V(2) receptor was also examined to evaluate the binding mode of this series of compounds.

Comparison of voiding function and nociceptive behavior in two rat models of cystitis induced by cyclophosphamide or acetone.

Aims: Nociceptive behavior and its relationship with bladder dysfunction were investigated in two cystitis models, which were induced by intraperitoneal (i.p.) injection of cyclophosphamide (CYP) or intravesical instillation of acetone, using freely moving, non-catheterized conscious rats.

Synthesis and structure-activity relationships of amide derivatives of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetic acid as selective arginine vasopressin V2 receptor agonists.

A series of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetamide derivatives was synthesized, and their structure-activity relationships were examined in order to identify potent and selective arginine vasopressin V(2) receptor agonists. Attempts to substitute other chemical groups in place of the 2-pyridilmethyl moiety of 1a led to the discovery that potent V(2) binding affinity could be obtained with a wide range of functional groups. This structural tolerance allowed for the manipulation of other attributes, such as selectivity against V(1a) receptor affinity or avoidance of the undesirable inhibition of cytochrome P450 (CYP), without losing potent affinity for the V(2) receptor.

Preparation of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetamide derivatives as novel arginine vasopressin V(2) receptor agonists.

The present work describes the discovery of novel series of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene)acetamide derivatives as arginine vasopressin (AVP) V(2) receptor agonists. By replacing the amide juncture in YM-35278 with a direct ring connection gave compound 10a, which acts as a V(2) receptor agonist. These studies provided the potent, orally active non-peptidic V(2) receptor agonists 10a and 10j.

Effects of intravesical instillation of resiniferatoxin on bladder function and nociceptive behavior in freely moving, conscious rats.

Purpose: A new animal model in which to concurrently evaluate bladder function and nociceptive behavior was developed using freely moving, noncatheterized, conscious rats to assess the nociceptive behavior responses induced by intravesical instillation of resiniferatoxin (Sigma) and its relationship with bladder dysfunction.

Materials And Methods: In female Sprague-Dawley rats resiniferatoxin (0, 0.3 and 3 microM) was instilled via a catheter that was temporarily inserted into the bladder through the urethra.

The differential contractile responses to capsaicin and anandamide in muscle strips isolated from the rat urinary bladder.

The contractile responses to capsaicin and anandamide, exogenous and endogenous agonists for transient receptor potential vanilloid receptor 1 (TRPV1), respectively, were investigated in muscle strips isolated from the rat urinary bladder. Capsaicin and anandamide produced concentration-dependent contractions of the muscle strips. The contractile response induced by capsaicin disappeared within approximately 20 min.

Pharmacological characterization of a new antimuscarinic agent, solifenacin succinate, in comparison with other antimuscarinic agents.

Solifenacin succinate [YM905; (3R)-1-azabicyclo[2.2.2]oct-3-yl(1S)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate monosuccinate] is a new muscarinic receptor antagonist developed for the treatment of overactive bladder.

Effect of tamsulosin on spontaneous bladder contraction in conscious rats with bladder outlet obstruction: comparison with effect on intraurethral pressure.

We investigated the effect of tamsulosin, an alpha(1)-adrenoceptor antagonist, on bladder function, especially spontaneous bladder contractions before micturition (premicturition contraction), in conscious rats with bladder outlet obstruction induced by partial urethral ligation, and compared the results with the effect on intraurethral pressure response in anesthetized rats. In obstructed rats, the alpha(1)-adrenoceptor antagonists tamsulosin, naftopidil and urapidil and non-selective alpha-adrenoceptor antagonist phentolamine inhibited premicturition contractions in a dose-dependent fashion. In contrast, yohimbine, an alpha(2)-adrenoceptor antagonist, and atropine, a muscarinic receptor antagonist, hardly inhibited them.

Effects of tamsulosin on hypogastric nerve stimulation-induced intraurethral pressure elevation in male and female dogs under anesthesia.

The aim of the present study was to investigate the effects of tamsulosin, an alpha(1)-adrenoceptor antagonist, on hypogastric nerve stimulation-induced intraurethral pressure elevation in anesthetized male and female dogs and to evaluate sex differences in these effects. Additionally, the effects of tamsulosin were also compared with those of other alpha(1)-adrenoceptor antagonists, namely prazosin, naftopidil and urapidil. Tamsulosin dose-dependently inhibited hypogastric nerve stimulation-induced intraurethral pressure elevation, with doses required to induce 50% inhibition of the elevation (ED(50) values) of 0.