A tryptamine analog with high affinity to the heart tissues is a potential antiarrhythmic agent.

A novel tryptamine analog, 1-methyl-3-[N-(3-indolyl)ethyl]carbamoyl-1,4-dihydropyridine (T-CDS) was synthesized and converted into a stable, solid complex with 2-hydroxypropyl-beta-cyclodextrin. An aqueous solution of the complex was given intravenously to dogs and the concentration of T-CDS and its corresponding quaternary (T-Q+) forms were monitored in the blood for 50 min. The effect of the drug on vital heart parameters was monitored throughout the studies. At the end of the experiment the dogs were sacrificed and the concentration of the quaternary pyridinium form (T-Q+) was determined in the different heart tissues, as well as in the kidney, liver, lung, brain, urine and cerebrospinal fluid. The compound was found to be selectively bound to the heart muscles and showed different concentrations in different heart tissues. The T-Q+ concentrations were much higher in the heart after administration of the dihydro form (T-CDS), than after administering T-Q+ directly. The compound was found to be active on certain vital signs of the cardiovascular system and could be an effective and safe antiarrhythmic agent.

Receptor binding studies of soft anticholinergic agents.

Receptor binding studies were performed on 24 soft anticholinergic agents and 5 conventional anticholinergic agents using 4 cloned human muscarinic receptor subtypes. The measured pK(i) values of the soft anticholinergic agents ranged from 6.5 to 9.5, with the majority being in the range of 7.5 to 8.5. Strong correlation was observed between the pK(i) s determined here and the pA 2 values measured earlier in guinea pig ileum contraction assays. The corresponding correlation coefficients (r2) were 0.80, 0.73, 0.81, and 0.78 for pK(i) (m1), pK(i) (m2), pK(i) (m3), and pK(i) (m4), respectively. Quantitative structure-activity relationship (QSAR) studies were also performed, and good characterization could be obtained for the soft anticholinergics containing at least 1 tropine moiety in their structure. For these compounds, the potency as measured by the pK i values was found to be related to geometric, electronic, and lipophilicity descriptors. A linear regression equation using ovality (O(e)), dipole moment (D), and a calculated log octanol-water partition coefficient (QLogP) gave reasonably good descriptions (r = 0.88) for the pK(i) (m3) values.

Ocular-specific delivery of timolol by sequential bioactivation of its oxime and methoxime analogs.

S-(-)- Timolol maleate was oxidized, using the modified Pfitzner-Mofatt method, to the corresponding keto analog, which was then coupled with either hydroxylamine or methoxyamine in the same reaction medium. The products separated, timolone oxime (TO) or timolone methoxime (TMO), were found to be a mixture of both E and Z isomers with the Z isomer in higher concentration. Both isomers could be separated on silica column. No isomerization of any of the isomers could be detected whether in buffers or biological fluids. TMO salts were found to be stable in slightly acidic buffer. The Z isomer of TMO is more stable than the E isomer. Both TO and TMO showed pronounced reduction of the intraocular pressure (IOP) in normotensive rabbits, when instilled into the conjunctival sac. Reduction of IOP caused by either TO or TMO was higher than the reduction produced with the same dose of timolol maleate. Equal doses of any of the TMO isomers or the mixture of isomers gave almost the same percent reduction of IOP. TMO and TO did not show cardiovascular effects when administered intravenously to rabbits or rats. Both are good candidates to be used for topical management of glaucoma without producing systemic side effects.

Ocular-specific chemical delivery systems of betaxolol for safe local treatment of glaucoma.

Novel ketomethoxime (BMO) and oxime (BO) analogs of betaxolol (B) were prepared through the oxidation of betaxolol, followed by quenching of the ketone with the appropriate oxyamine. The Z isomers were kinetically favored and thermodynamically more stable. Isomerization to reach an equilibrium mixture of Z/E was observed for all pure isomers in buffers. Equilibration is much faster, however in biological fluids. Ocular administration of any of the oxime derivatives, delivers betaxolol specifically to the eye tissues, with the highest concentration in the iris ciliary body. Both BMO and BO, when applied topically, showed marked reduction of intraocular pressure (IOP) in normotensive rabbits. No effect on isoproterenol-induced tachycardia in rabbits and rats were observed, even after iv. administration. Very mild eye irritation, which was less than that of betaxolol hydrochloride, was observed particularly with BMO maleate, which is an excellent candidate for safe treatment of glaucoma.

Synthesis and investigation of N4-substituted cytarabine derivatives as prodrugs.

Esters of Cytarabine-N4-carboxylates 2a-i and succinamates 3a-f were synthesized as prodrugs of cytarabine (Ara-C) with the aim of developing improved derivatives for oral or parentral administration. At pH 2 series 2 showed relative higher stability than 3, while both series of esters revealed matched stability at pH 7. All esters were susceptible to enzymatic hydrolysis by rat plasma and liver homogenate with half lives ranged from 0.14 h to 12 d, and showed improved stability against cytidine deaminase. A parabolic relation was shown between Kobs of enzymatic hydrolysis and Vw. All compounds are more lipophilic than the parent drug, Ara-C.

Synthesis and evaluation of a redox chemical delivery system for brain-enhanced dopamine containing an activated carbamate-type ester.

A chemical delivery system (CDS) for enhanced delivery of dopamine to brain tissue, based on a dihydropyridine<==>pyridinium salt redox system, was modified to include an activated carbamate ester. The dihydronicotinate moiety was chemically attached to the amino group of dopamine (DA) by acylation with chloroethyl chloroformate, followed by condensation with sodium nicotinate under mild conditions. The product was selectively N-alkylated at the pyridine ring and subjected to regioselective reduction to the corresponding 1,4-dihydropyridine derivative, DA-CDSac. In vitro stability of the new compound was studied in phosphate buffers at mild acidic, physiological, and mild alkaline pH values. Oxidation studies showed facile conversion of the dihydronicotinate, DA-CDSac, is readily converted to the corresponding quaternary salt, both chemically and enzymatically. In vivo studies in rats did not detect sustained increases in brain levels of the quaternary salt after i.v. dosing with DA-CDSac. However, the new CDS appeared to change spontaneous locomotor activity in rats after i.v. administration which may be due to altered central DA neuronal activity.

HPLC Determination of some antibilharzial antimonials by extraction of antimony.

The antimonial drug (antimony potassium tartrate, antimony piperazine tartrate or antimony lithium thiomaleate) in aqueous solution or biological fluid is treated with sodium diethyldithiocarbamate in the presence of a suitable masking reagent, the pH is adjusted to 9 +/- 0.5. and the antimony complex extracted with n-hexane and determined by reversed-phase HPLC with an ODS column and detection at 254 nm. The limits of detection are 20 ng (for antimony potassium tartrate and antimony lithium thiomaleate) and 16 ng (for antimony piperazine tartrate).

HPLC determination of niridazole.

A high-performance liquid chromatographic method has been developed for the determination of niridazole in bulk form and in pharmaceutical dosage form. A reversed-phase system, based on an octadecylsilane-bonded stationary phase and a 60:40 v/v methanol/water mobile phase, is used. The detector response at 370 nm is linearly related to the amount injected, over a wide range. The method is sensitive, simple, rapid and precise.

Imidazo[2,1-b]benzothiazoles. II. Synthesis and antiinflammatory activity of some imidazo[2,1-b]benzothiazoles.

3-[2-[p-(Un)substituted phenyl]imidazo [2,1-b]benzothiazol-3- yl]propionic acid derivatives (2a--e) were prepared via the interaction of the corresponding 2-[p-(un)substituted phenyl]imidazo[2,1-b]benzothiazoles (1a--e) with acrylic acid in the presence of acetic anhydride and acetic acid. Esterification of 2a--e produced methyl esters (3a--e). Upon the interaction of 3a with m-chloroperbenzoic acid, the S-dioxide (4a) was obtained. Compound 5a was prepared from 4a by alkaline hydrolysis. Vilsmeier formylation for 1a--e produced novel [2-[p-(un)substituted phenyl]imidazo[2,1-b]benzothiazol-3- yl]formaldehyde derivatives (6a--e). Derivatives 6a--e reacted with ethyl bromoacetate to give ethyl 3-hydroxy-3-[2-[p-(un)substituted phenyl]imidazo[2,1-b]benzothiazol- 3-yl]propionate esters (7a--e). Compound dl-7a was resolved with l-(+)-tartaric acid. Compounds 2a--e showed weak or no activity in the carrageein-induced paw edema assay. Compound 4a significantly inhibited the leakage of pontamine-sky blue dye into the peritoneal cavity of mice, in the capillary permeability inhibition assay. Compound 5a inhibited the writhing by 62% in the acetic acid-induced writhing assay.

Improved delivery through biological membranes XIV: Brain-specific, sustained delivery of testosterone using a redox chemical delivery system.

The dihydropyridine in equilibrium pyridinium salt redox delivery system was used for the specific delivery and sustained release of testosterone in the brain. Administration of the N-methyl-1,4-dihydro nicotinate ester of testosterone in female rats gave high and sustained brain levels of the corresponding quaternary ester, testosterone trigonellinate. This contrasted with rapid elimination from the general circulation. Release of testosterone "locked into" brain as the quaternary salt was sustained, t1/2 = 20 h.

Improved delivery through biological membranes. 13. Brain-specific delivery of dopamine with a dihydropyridine in equilibrium with pyridinium salt type redox delivery system.

The dihydropyridine in equilibrium with pyridinium salt type redox delivery system was used for the brain-specific delivery of dopamine. In vivo administration of the catechol-protected dopamine coupled with 1,4-dihydrotrigonelline as the carrier resulted in brain-specific, high and sustained concentrations of the 1-methyl-3-[N-[beta-(3,4-dihydroxyphenyl)ethyl]carbamoyl]pyridinium salt, the direct dopamine precursor, locked in the brain for many hours, while systemic concentration decreased fast, with a t 1/2 of less than 30 min. Significant dopaminergic activity was observed in the brain, which was sustained for hours.

Improved delivery through biological membranes. 11. A redox chemical drug-delivery system and its use for brain-specific delivery of phenylethylamine.

A dihydropyridine in equilibrium pyridinium salt type redox system is described as a general and flexible method for site-specific and sustained delivery of drugs to the brain. According to this, a biologically active compound linked to a lipoidal dihydropyridine carrier easily penetrates the blood-brain barrier. Oxidation of the carrier part in vivo to the ionic pyridinium salt prevents its elimination from the brain, while elimination from the general circulation is accelerated. Subsequent cleavage of the quaternary carrier-drug species results in sustained delivery of the drug in the brain and facile elimination of the carrier part. The concept is illustrated with phenethylamine as the drug and trigonelline as the quaternary carrier. One injection to rats of 1-methyl-3-(N-phenethylcarbamoyl)-1,4-dihydropyridine resulted in continuous build up in the brain of the corresponding 1-methyl-3-(N-phenethylcarbamoyl)pyridinium salt, reaching a maximum at about 80 min. At this time, the general circulation was practically void of either compound, while the accumulated carrier-drug species provided a source for sustained drug delivery only in the brain.

Site-specific, sustained release of drugs to the brain.

A dihydropyridine-pyridinium salt type of redox system is used in a general and flexible method for the site-specific or sustained delivery (or both) of drugs to the brain. A biologically active compound linked to a lipoidal dihydropyridine carrier easily penetrates the blood-brain barrier. Oxidation of the carrier part in vivo to the ionic pyridinium salt prevents its elimination from the brain, while elimination from the general circulation is accelerated. Subsequent cleavage of the quaternary carrier-drug species results in sustained delivery of the drug in the brain and facile elimination of the carrier part.