ABSTRACT
The new flavone derivative REC 15/2053, a compound with spasmolytic activity on the lower urinary tract, was examined for its in vitro interaction with alpha- and beta-noradrenergic receptors, dopaminergic, muscarinic, serotoninergic, and opiate receptors, and calcium-channel binding sites labeled with 1,4-dihydropyridines from normal rat brain. All the investigated receptors are directly or indirectly involved in the nervous control of the lower urinary tract functions. The activity of REC 15/2053 on these receptors was studied in comparison to the most common drugs used in the management of urinary bladder disorders such as flavoxate, emepronium bromide, oxybutynin, terodiline, and imipramine. REC 15/2053 showed only weak binding to [3H]nitrendipine sites (IC50 = 14 microM) and muscarinic receptors (IC50 = 18 microM), whereas flavoxate was slightly active only at muscarinic receptors (IC50 = 12.2 microM). Emepronium bromide, oxybutynin, and terodiline were active only at muscarinic receptors, with IC50 values of 236, 5.4, and 588 nM, respectively. Oxybutynin showed a weak affinity to [3H]nitrendipine binding sites (IC50 = 44.4 microM). Imipramine was active at alpha 1-adrenergic and muscarinic receptors (IC50 = 248 and 653 nM, respectively). The activity of REC 15/2053 at muscarinic receptors and 1,4-dihydropyridine binding sites seems too low to account for its mechanism of action.
Subject(s)
Flavonoids/metabolism , Flavoxate/metabolism , Parasympatholytics/metabolism , Receptors, Drug/metabolism , Urinary Bladder/drug effects , Animals , Binding, Competitive/drug effects , Brain Chemistry , Flavoxate/analogs & derivatives , Flavoxate/pharmacology , In Vitro Techniques , Male , Nitrendipine/metabolism , Quinuclidinyl Benzilate , Rats , Rats, Inbred StrainsABSTRACT
The pharmacological properties of 3-methylflavone-8-carboxylic acid (MFCA), the main metabolite of flavoxate, have been studied in vitro and in vivo. MFCA did not display antispasmodic activity on isolated organs contractions induced by histamine, acetylcholine or CaCl2, nor did it exhibit significant affinity for the rat brain alpha- and beta-adrenergic, serotoninic, muscarinic, D2, opiate and Ca2+ receptors. However, it showed a remarkable phosphodiesterase (PDE) inhibiting activity. Moreover in vivo studies indicate an interesting activity of MFCA which inhibited the rat urinary bladder voiding contractions, increased bladder volume capacity and decreased micturition pressure in the rat cystometric recordings. The activity of MFCA in the two in vivo experimental models, probably related to cAMP-PDE inhibitory properties, suggests that flavoxate's therapeutical potential might be partially sustained by its main metabolite.
Subject(s)
Flavonoids/pharmacology , Flavoxate/pharmacology , 3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Animals , Calcium Channel Blockers , Female , Flavoxate/analogs & derivatives , Guinea Pigs , In Vitro Techniques , Male , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Rats , Rats, Inbred Strains , Receptors, Drug/drug effects , Urinary Bladder/drug effectsABSTRACT
The relationship between the brain concentration of denzimol and its anticonvulsant activity was studied in mice after acute and repeated administration (14 days) of this drug to mice. Anticonvulsant activity was assessed against maximal electroshock seizures (MES). When denzimol was administered at 30 mg/kg p.o. to repeatedly treated mice, its brain concentration and anticonvulsant activity were reduced in comparison to non-treated mice and t1/2 beta was significantly changed from 2.10 to 1.53 hr. Tonic hindlimb extension was completely abolished at a brain denzimol concentration higher than 15 mcg/g, whereas the minimum effective brain concentration was between 2-3 mcg/g both in acute and repeatedly treated animals. The brain concentration of denzimol is closely correlated with its anticonvulsant effect both in acute and repeatedly treated animals. Furthermore these findings seem to suggest that the decreased anticonvulsant activity of denzimol, following repeated administrations, might be due to a development of pharmacokinetic tolerance.
Subject(s)
Anticonvulsants/metabolism , Brain/metabolism , Imidazoles/metabolism , Animals , Anticonvulsants/administration & dosage , Dose-Response Relationship, Drug , Drug Administration Schedule , Electroshock , Imidazoles/administration & dosage , Mice , Seizures/prevention & controlABSTRACT
The relationship between plasma, brain and cerebellum concentrations of Denzimol a new anticonvulsant agent, and its anticonvulsant and neurotoxic effects were studied in the rat. Sixty minutes after oral administration, a high brain/plasma concentration ratio of 10:1 was found. Mean plasma, brain and cerebellum half-lives of the drug were 8.4, 7.1 and 9.2 hr, respectively. The anticonvulsant activity of the drug was examined by maximal electroshok seizures (MES). Neurotoxicity was determined both by the rotarod performance test and by behavioural observation. Denzimol was effective against MES, in the ranges of 0.8-5 micrograms/ml and 10-50 micrograms/ml for plasma and brain concentrations, respectively, without causing clear signs of neurological toxicity. It is concluded that the anticonvulsant and neurotoxic effects of denzimol are correlated to its plasma and brain concentrations.
