piperidines and oxybutynin

To investigate the effects of tissue stretch and muscarinic receptor stimulation on the spontaneous activity of the urothelium/lamina propria and identify the specific receptor subtype mediating these responses.. Isolated strips of porcine urothelium with lamina propria were set up for in vitro recording of contractile activity. Muscarinic receptor subtype-selective antagonists were used to identify the receptors influencing the contractile rate responses to stretch and stimulation with carbachol.. Isolated strips of urothelium with lamina propria developed spontaneous contractions (3.7 cycles/min) that were unaffected by tetrodotoxin, Nω-nitro-L-arginine, or indomethacin. Carbachol (1 μM) increased the spontaneous contractile rate of these tissue strips by 122% ± 27% (P < .001). These responses were significantly depressed in the presence of the M3-selective muscarinic antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (10-30 nM) but were not affected by the M1-selective antagonist pirenzepine (30-100 nM) or the M2-selective antagonist methoctramine (0.1-1 μM). Stretching of the tissue also caused an increase in the spontaneous contractile rate, and these responses were abolished by atropine (1 μM) and low concentrations of 4-diphenylacetoxy-N-methylpiperidine methiodide (10 nM). Darifenacin, oxybutynin, tolterodine, and solifenacin (1 μM) all significantly depressed the frequency responses to carbachol (1 μM).. The urothelium with the lamina propria exhibits a spontaneous contractile activity that is increased during stretch. The mechanism appears to involve endogenous acetylcholine release acting on M3 muscarinic receptors. Anticholinergic drugs used clinically depress the responses of these tissues, and this mechanism might represent an additional site of action for these drugs in the treatment of bladder overactivity.

Topics: Animals; Atropine; Benzhydryl Compounds; Benzofurans; Carbachol; Cresols; Diamines; Mandelic Acids; Mucous Membrane; Muscarinic Antagonists; Muscle Contraction; Phenylpropanolamine; Piperidines; Pirenzepine; Pyrrolidines; Quinuclidines; Receptor, Muscarinic M3; Solifenacin Succinate; Stress, Mechanical; Swine; Tetrahydroisoquinolines; Tolterodine Tartrate; Urinary Bladder; Urothelium

Topics: Adrenergic beta-Agonists; Albuterol; Amantadine; Analgesics, Non-Narcotic; Androstadienes; Aromatase Inhibitors; Asthma; Bronchodilator Agents; Donepezil; Drug Therapy, Combination; Female; Fluticasone; Food Hypersensitivity; Humans; Indans; Interferons; Latex Hypersensitivity; Letrozole; Mandelic Acids; Middle Aged; Multiple Sclerosis; Nebulizers and Vaporizers; Nitriles; Nootropic Agents; Parasympatholytics; Paresthesia; Piperidines; Respiratory Function Tests; Salmeterol Xinafoate; Thyroxine; Triazoles

1. Muscarinic cholinoceptors (MChR) in freshly dispersed rat salivary gland (RSG) cells were characterized using microphysiometry to measure changes in acidification rates. Several non-selective and selective muscarinic antagonists were used to elucidate the nature of the subtypes mediating the response to carbachol. 2. The effects of carbachol (pEC(50) = 5.74 +/- 0.02 s.e.mean; n = 53) were highly reproducible and most antagonists acted in a surmountable, reversible fashion. The following antagonist rank order, with apparent affinity constants in parentheses, was noted: 4-DAMP (8.9)= atropine (8.9) > tolterodine (8.5) > oxybutynin (7.9) > S-secoverine (7.2) > pirenzepine (6.9) > himbacine (6.8) > AQ-RA 741 (6.6) > methoctramine (5.9). 3. These studies validate the use of primary isolated RSG cells in microphysiometry for pharmacological analysis. These data are consistent with, and extend, previous studies using alternative functional methods, which reported a lack of differential receptor pharmacology between bladder and salivary gland tissue. 4. The antagonist affinity profile significantly correlated with the profile at human recombinant muscarinic M(3) and M(5) receptors. Given a lack of antagonists that discriminate between M(3) and M(5), definitive conclusion of which subtype(s) is present within RSG cells cannot be determined.

Topics: Alkaloids; Animals; Atropine; Benzhydryl Compounds; Benzodiazepinones; Binding, Competitive; Biosensing Techniques; Carbachol; Cholinergic Agonists; Cresols; Diamines; Dose-Response Relationship, Drug; Furans; Male; Mandelic Acids; Muscarinic Antagonists; Naphthalenes; Phenethylamines; Phenylpropanolamine; Piperidines; Pirenzepine; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic; Submandibular Gland; Tolterodine Tartrate

The effects of a new tachykinin NK(1) receptor antagonist, (aR, 9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10, 11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g] [1, 7]naphthyridine-6,13-dione (TAK-637), on the micturition reflex were compared with those of drugs used for abnormally frequent micturition or incontinence. TAK-637 showed a characteristic effect on the distension-induced rhythmic bladder contractions in guinea pigs. The systemic administration of TAK-637 decreased the number but not the amplitude of the distension-induced rhythmic bladder contractions. A similar effect was observed in animals in which the spinal cord had been severed. TAK-637 also inhibited the micturition reflex induced by topical application of capsaicin onto the surface of bladder dome. From these results, it is concluded that TAK-637 inhibits sensory transmissions from the bladder evoked by both physiological and nociceptive stimuli by blocking tachykinin NK(1) receptors, possibly at the level of the spinal cord. On the other hand, the other drugs such as oxybutynin, tolterodine, propiverine, and inaperisone showed no effects on the frequency of the distension-induced rhythmic bladder contractions but decreased the contraction amplitude. Therefore, TAK-637 may represent a new class of drugs, which would be effective for abnormally frequent micturition without causing voiding difficulties due to decreased voiding pressure.

Topics: Animals; Benzhydryl Compounds; Benzilates; Capsaicin; Cholinergic Antagonists; Cresols; Dilatation; Dose-Response Relationship, Drug; Guinea Pigs; Male; Mandelic Acids; Muscarinic Antagonists; Muscle Contraction; Muscle Relaxants, Central; Naphthyridines; Parasympatholytics; Phenylpropanolamine; Piperidines; Propiophenones; Receptors, Tachykinin; Reflex; Tolterodine Tartrate; Urinary Bladder; Urination

With the aim of improving of the efficacy and decreasing the side effects of oxybutynin (1), N-[(tetrahydro-3- or 4-pyridyl)methyl]-, N-(4-piperidyl)-, and N-(3- or 4-piperidylalkyl)-2-hydroxyacetamides (3a-n, 4a-g) and the related carboxamides (3o-r, 4h-k, 13', 17) were synthesized and evaluated for inhibitory activity against urinary bladder rhythmic contraction in rats and for mydriatic activity in rats. Some of these compounds were superior to oxybutynin in both inhibitory activity against bladder contraction and selectivity between inhibitory activity against bladder contraction and mydriatic activity. Among them, N-[(1,2,3,6-tetrahydro-4-pyridyl)methyl]- and N-[(1,2,3,6-tetrahydro-1-methyl-4-pyridyl)methyl]-2-hydroxy-2,2- diphenylacetamide (3e, 3f) exhibited the most potent inhibitory activity against bladder contraction (ED30 = 0.005 and 0.003 mg/kg i.v., respectively). Judging from the effect of 3e on detrusor contraction in vitro in guinea-pigs, it appeared that the inhibitory activity of 3e against bladder contraction in vivo was related mainly to its inhibitory activity against detrusor contraction in vitro induced with carbachol (antimuscarine-like activity). The selectivity (20-fold) of 3e between inhibitory activity against bladder contraction and mydriatic activity was greatly superior to that (0.48-fold) of oxybutynin. Compound 3e was synthesized by debenzylation (method E or F) of the corresponding N-[[1-(4-methoxybenzyl)-tetrahydro-4-pyridyl]methyl] derivative (3k), which was prepared by acylation (method B) of the corresponding (tetrahydro-4-pyridyl)methylamine (7k) or by reduction (method D) of the corresponding pyridinium chloride (14k) with NaBH4.

Topics: Acetamides; Animals; In Vitro Techniques; Mandelic Acids; Muscle Contraction; Muscle, Smooth; Mydriasis; Piperidines; Rats; Urinary Bladder; Urination Disorders