Lower urinary tract disorders include disorders affecting continence (stress urinary incontinence, urge urinary incontinence, and benign prostatic hyperplasia) and male erectile dysfunction. Although ...none of these conditions are fatal, they affect overall quality of life. Throughout modern medicine the treatment of these conditions was limited to psychological counseling or surgical intervention. In recent years, research defining the physiological mechanisms of continence and male sexual function has aided in the pharmacologic design of approaches to these conditions. These agents can act both centrally or on the peripheral genitourinary smooth muscle to alleviate disease symptoms. Incontinence is primarily treated with agents that act directly on the bladder smooth muscle such as muscarinic antagonists. However, afferent blockade to attenuate the spinalbulbospinal reflex pathway including mixed norepinephrine/serotonin reuptake inhibitors may provide a key breakthrough. Erectile dysfunction treatment has been revolutionized via the discovery of the nitric oxide pathway and phosphodiesterase 5 inhibitors. New peripheral targets as well as centrally acting agents represent potential emerging therapies. In this review, the pharmacologic basis of treatment of these disorders is discussed with special emphasis on emerging new therapeutics.
Alterations in the myogenic activity of the bladder smooth muscle are thought to serve as a basis for the involuntary detrusor contractions associated with the overactive bladder. Activation of ...ATP-sensitive K(+) (K(ATP)) channels has been recognized as a potentially viable mechanism to modulate membrane excitability in bladder smooth muscle. In this study, we describe the preclinical pharmacology of (-)-(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno3,2-bquinolin-8(4H)-one 1,1-dioxide (A-278637), a novel 1,4-dihydropyridine K(ATP) channel opener (KCO) that demonstrates enhanced bladder selectivity for the suppression of unstable bladder contractions in vivo relative to other reference KCOs. A-278637 activated K(ATP) channels in bladder smooth muscle cells in a glyburide (glibenclamide)-sensitive manner as assessed by fluorescence membrane potential assays using bis-(1,3-dibutylbarbituric acid)trimethine oxonol (EC(50) = 102 nM) and by whole cell patch clamp. Spontaneous (myogenic) phasic activity of pig bladder strips was suppressed (IC(50) = 23 nM) in a glyburide-sensitive manner by A-278637. A-278637 also inhibited carbachol- and electrical field-stimulated contractions of bladder strips, although the respective potencies were 8- and 13-fold lower compared with inhibition of spontaneous phasic activity. As shown in the accompanying article Brune ME, Fey TA, Brioni JD, Sullivan JP, Williams M, Carroll WA, Coghlan MJ, and Gopalakrishnan M (2002) J Pharmacol Exp Ther 303:387-394, A-278637 suppressed myogenic contractions in vivo in a model of bladder instability with superior selectivity compared with other KCOs, WAY-133537 (R)-4-3,4-dioxo-2-(1,2,2-trimethyl-propylamino)cyclobut-1-enylamino-3-ethyl-benzonitrile and ZD6169 (S)-N-(4-benzoylphenyl)3,3,3-trifluro-2hydroxy-2-methyl-priopionamide. A-278637 did not interact with other ion channels, including L-type calcium channels or other neurotransmitter receptor systems. The pharmacological profile of A-278637 represents an attractive basis for further investigations of selective K(ATP) channel openers for the treatment of overactive bladder via myogenic etiology.
Acid Sensing Ion Channels (ASICs) are a group of sodium-selective ion channels that are activated by low extracellular pH. The role of ASIC in disease states remains unclear partly due to the lack of ...selective pharmacological agents. In this report, we describe the effects of A-317567, a novel non-amiloride blocker, on three distinct types of native ASIC currents evoked in acutely dissociated adult rat dorsal root ganglion (DRG) neurons. A-317567 produced concentration-dependent inhibition of all pH 4.5-evoked ASIC currents with an IC
50 ranging between 2 and 30
μM, depending upon the type of ASIC current activated. Unlike amiloride, A-317567 equipotently blocked the sustained phase of ASIC3-like current, a biphasic current akin to cloned ASIC3, which is predominant in DRG. When evaluated in the rat Complete Freud's Adjuvant (CFA)-induced inflammatory thermal hyperalgesia model, A-317567 was fully efficacious at a dose 10-fold lower than amiloride. A-317567 was also potent and fully efficacious when tested in the skin incision model of post-operative pain. A-317567 was entirely devoid of any diuresis or natriuresis activity and showed minimal brain penetration. In summary, A-317567 is the first reported small molecule non-amiloride blocker of ASIC that is peripherally active and is more potent than amiloride in vitro and in vivo pain models. The discovery of A-317567 will greatly help to enhance our understanding of the physiological and pathophysiological role of ASICs.
The histamine H(4) receptor (H(4)R) is expressed primarily on cells involved in inflammation and immune responses. To determine the potential role of H(4)R in pain transmission, the effects of ...JNJ7777120, a potent and selective H(4) antagonist, were characterized in preclinical pain models. Administration of JNJ7777120 fully blocked neutrophil influx observed in a mouse zymosan-induced peritonitis model (ED(50)=17 mg/kg s.c., 95% CI=8.5-26) in a mast cell-dependent manner. JNJ7777120 potently reversed thermal hyperalgesia observed following intraplantar carrageenan injection of acute inflammatory pain (ED(50)=22 mg/kg i.p., 95% CI=10-35) in rats and significantly decreased the myeloperoxide activity in the carrageenan-injected paw. In contrast, no effects were produced by either H(1)R antagonist diphenhydramine, H(2)R antagonists ranitidine, or H(3)R antagonist ABT-239. JNJ7777120 also exhibited robust anti-nociceptive activity in persistent inflammatory (CFA) pain with an ED(50) of 29 mg/kg i.p. (95% CI=19-40) and effectively reversed monoiodoacetate (MIA)-induced osteoarthritic joint pain. This compound also produced dose-dependent anti-allodynic effects in the spinal nerve ligation (ED(50)=60 mg/kg) and sciatic nerve constriction injury (ED(50)=88 mg/kg) models of chronic neuropathic pain, as well as in a skin-incision model of acute post-operative pain (ED(50)=68 mg/kg). In addition, the analgesic effects of JNJ7777120 were maintained following repeated administration and were evident at the doses that did not cause neurologic deficits in rotarod test. Our results demonstrate that selective blockade of H(4) receptors in vivo produces significant anti-nociception in animal models of inflammatory and neuropathic pain.
Background and purpose: The histamine H3 receptor antagonist radioligand 3H‐A‐349821 was characterized as a radiotracer for assessing in vivo receptor occupancy by H3 receptor antagonists that ...affect behaviour. This model was established as an alternative to ex vivo binding methods, for relating antagonist H3 receptor occupancy to blood levels and efficacy in preclinical models.
Experimental approach: In vivo cerebral cortical H3 receptor occupancy by 3H‐A‐349821 was determined in rats from differences in 3H‐A‐349821 levels in the isolated cortex and cerebellum, a brain region with low levels of H3 receptors. Comparisons were made to relate antagonist H3 receptor occupancy to blood levels and efficacy in a preclinical model of cognition, the five‐trial inhibitory avoidance response in rat pups.
Key results: In adult rats, 3H‐A‐349821, 1.5 µg·kg−1, penetrated into the brain and cleared more rapidly from cerebellum than cortex; optimally, 3H‐A‐349821 levels were twofold higher in the latter. With increasing 3H‐A‐349821 doses, cortical H3 receptor occupancy was saturable with a binding capacity consistent with in vitro binding in cortex membranes. In studies using tracer 3H‐A‐349821 doses, ABT‐239 and other H3 receptor antagonists inhibited H3 receptor occupancy by 3H‐A‐349821 in a dose‐dependent manner. Blood levels of the antagonists corresponding to H3 receptor occupancy were consistent with blood levels associated with efficacy in the five‐trial inhibitory avoidance response.
Conclusions and implications: When employed as an occupancy radiotracer, 3H‐A‐349821 provided valid measurements of in vivo H3 receptor occupancy, which may be helpful in guiding and interpreting clinical studies of H3 receptor antagonists.
SAR (structure−activity relationship) studies of triazafluorenone derivatives as potent mGluR1 antagonists are described. The triazafluorenone derivatives are non-amino acid derivatives and ...noncompetitive mGluR1 antagonists that bind at a putative allosteric recognition site located within the seven-transmembrane domain of the receptor. These triazafluorenone derivatives are potent, selective, and systemically active mGluR1 antagonists. Compound 1n, for example, was a very potent mGluR1 antagonist (IC50 = 3 nM) and demonstrated full efficacy in various in vivo animal pain models.
Background and purpose:
The histamine H
4
receptor is widely expressed in cells of immune origin and has been shown to play a role in a variety of inflammatory processes mediated by histamine. In ...this report, we describe the
in vitro
and
in vivo
anti‐inflammatory properties of a potent histamine H
4
receptor antagonist, A‐940894 (4‐piperazin‐1‐yl‐6,7‐dihydro‐5H‐benzo6,7cyclohepta1,2‐dpyrimidin‐2‐ylamine).
Experimental approach:
We have analysed the pharmacological profile of A‐940894 at mouse native, rat recombinant and human recombinant and native, histamine H
4
receptors by radioligand binding, calcium mobilization, mast cell shape change, eosinophil chemotaxis assays and in the mouse model of zymosan‐induced peritonitis.
Key results:
A‐940894 potently binds to both human and rat histamine H
4
receptors and exhibits considerably lower affinity for the human histamine H
1
, H
2
or H
3
receptors. It potently blocked histamine‐evoked calcium mobilization in the fluorometric imaging plate reader assays and inhibited histamine‐induced shape change of mouse bone marrow‐derived mast cells and chemotaxis of human eosinophils
in vitro
. In a mouse mast cell‐dependent model of zymosan‐induced peritonitis, A‐940894 significantly blocked neutrophil influx and reduced intraperitoneal prostaglandin D
2
levels. Finally, A‐940894 has good pharmacokinetic properties, including half‐life and oral bioavailability in rats and mice.
Conclusions and Implications:
These data suggest that A‐940894 is a potent and selective histamine H
4
receptor antagonist with pharmacokinetic properties suitable for long‐term
in vivo
testing and could serve as a useful tool for the further characterization of histamine H
4
receptor pharmacology.
Activation of soluble guanylate cyclase with a subsequent increase in intracellular levels of cyclic guanosine monophosphate is necessary for normal erection. In vascular tissue ...3(5′-hydroxymethyl-2′-furyl-1-benzyl indazole (YC-1) (Abbott Laboratories, North Chicago, Illinois) has been shown to stimulate soluble guanylate cyclase independent of nitric oxide. We studied whether YC-1 modulates erectile responses in the rat.
The effects of YC-1 given intracavernously or intraperitoneally on intracavernous pressure were investigated in rats. Functional effects of YC-1 on neuronal and endothelial nitric oxide relaxations were studied in 3 × 10
−6 M. 1-noradrenaline contracted preparations of rat isolated corpus cavernosum.
Intracavernous YC-1 (10 μmol. kg.
−1) produced erectile responses with a mean intracavernous pressure plus or minus standard error of mean of 81 ± 17 cm. water (p <0.001) and a mean duration of 7.1 ± 3.3 minutes (p <0.001). YC-1 (10 μmol. kg.
−1) given intraperitoneally also increased the amplitude and duration of erectile responses to cavernous nerve stimulation. Mean peak intracavernous pressure increased from 63 ± 6 to 102 ± 16 cm. water (p <0.05). Erections induced by a submaximal dose of 25 μg. kg.
−1 apomorphine s.c. increased in number after 10 μmol. kg.
−1 YC-1 intraperitoneally (p <0.05). In vitro nerve induced relaxant responses were enhanced by increasing concentrations of YC-1. Relaxations at 20 Hz. were increased from a mean of 9% ± 5% to 52% ± 5% at a YC-1 concentration of 10
−5 M. (p <0.001). At this concentration carbachol induced relaxations were enhanced from a mean of 19% ± 3% to 40% ± 9% (p <0.05).
YC-1 can evoke erectile responses when given intracavernously and it enhances erections induced by cavernous nerve stimulation and apomorphine when given systemically. In vitro YC-1 enhances electrically evoked relaxations in rat corpus cavernosum. YC-1 represents an interesting pharmacological principle that may be useful for treating erectile dysfunction.
Apomorphine, a nonselective dopamine receptor agonist, facilitates penile erection and is effective in patients suffering from erectile dysfunction. The specific dopamine receptor subtype(s) ...responsible for its erectogenic effect is not known. Here we report that the dopamine D
4
receptor plays a role in the regulation of penile function. ABT-724 is a selective dopamine D
4
receptor agonist that activates human dopamine D
4
receptors with an EC
50
of 12.4 nM and 61% efficacy, with no effect on dopamine D
1
, D
2
, D
3
, or D
5
receptors. ABT-724 dose-dependently facilitates penile erection when given s.c. to conscious rats, an effect that is blocked by haloperidol and clozapine but not by domperidone. A proerectile effect is observed after intracerebroventricular but not intrathecal administration, suggesting a supraspinal site of action. s.c. injections of ABT-724 increase intracavernosal pressure in awake freely moving rats. In the presence of sildenafil, a potentiation of the proerectile effect of ABT-724 is observed in conscious rats. The ability of ABT-724 to facilitate penile erection together with the favorable side-effect profile indicates that ABT-724 could be useful for the treatment of erectile dysfunction.
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