Drug design and delivery最新文献

The inhibitory effects of a series of nonspecific local anesthetics on batrachotoxin-elicited sodium flux, batrachotoxin-elicited phosphoinositide breakdown, and on the binding of [3H]batrachotoxin-A 20 alpha-benzoate to sodium channels in guinea pig cerebral cortical synaptoneurosomes are shown to be well-correlated with the molecular size and the hydrophobic character of the molecules. These correlations lead us to suggest that the drug-receptor interaction involves a dispersion interaction, and that the overall effects of local anesthetics is dependent upon their ability to reach the receptor site.

There are wide applications of great importance for the improved and efficient administration of many materials--particularly in the pharmaceutical area. The introduction of novel polymeric materials and related formulation technologies now provide a versatile means for the precisely controlled delivery of many physiologically active substances. A further advantage is a decrease in patient discomfort and compliance, and decreased side-effects.

3-Alkoxycarbonylaminomethylcarbonylamino-4-(arylcarbonyl)pyr idines--in which the chlorophenyl ring of dipeptidylaminobenzophenones is replaced by a pyridyl ring--were synthesized and evaluated as anticonvulsants using subcutaneous pentylenetetrazole (scPTZ) and maximal electroshock (MES) induced seizure screening tests. The substituent on the aryl ring of the 4-arylcarbonyl moiety was a determinant of activity in both tests, the potency order of substituents being generally 2-F greater than 2-H greater than 2-Cl. Compounds possessing a 3-benzyloxycarbonylaminomethylcarbonylamino substituent exhibited moderate activity in the scPTZ test, whereas all 3-tert-butoxycarbonylaminomethylcarbonylamino derivatives were inactive. The test results in the scPTZ screen suggest that the 3-benzyloxycarbonylaminomethylcarbonyl(N-methyl)amino compounds may undergo biotransformation, at least in part, to pyrido[3,4-e]-1,4-diazepin-2-ones. 3-Alkoxycarbonylaminomethylcarbonyl(N-methyl)amino-substituted compounds were always more potent than analogous 3-alkoxycarbonylaminomethylcarbonylamino-substituted compounds in the scPTZ test, whereas they were equipotent in the MES screen. Following oral administration, 3-benzyloxycarbonylaminomethylcarbonyl(N-methyl)amino-4-(2-chlorob enzoyl) pyridine exhibited a potency greater than that of valproic acid but less than that of clonazepam in the rat scPTZ screening test. 3-Benzyloxycarbonylaminomethylcarbonylamino-4-(2-fluorobenzoyl)pyr idine was the most potent compound in the rat oral MES screening test, exhibiting an activity greater than that of clonazepam but less than that of phenytoin. The 3-alkoxycarbonylaminomethylcarbonylamino-4-(arylcarbonylpyridin es had moderate affinity for the benzodiazepine receptor site(s); the IC50s in displacing 10 nM [3H]flunitazepam were in the 0.37-15.11 microM range (clonazepam = 0.003 microM).

In this review, the properties, pharmaceutical profile, and metabolism of Azone are described, and the mechanism of its action in facilitating transdermal drug delivery is discussed. It is concluded that the compound is safe for human use, and of value in enhancing the cutaneous absorption of many types of drugs.

Compounds of the type Het-CH2-S-CH2-CH2-Y were prepared, in which Het was 2-, 3- or 4-pyridyl, and Y was a derivative of 2-cyano-1,1-iminodiamine or 2-nitro-1,1-ethenediamine in which the terminal nitrogen was incorporated into a 1,4-dihydropyridine ring (general structure 7; X = NCN or CHNO2). Pharmacological testing using the histamine-induced guinea pig atrial chronotropic response indicated that the pyridyl substituent position was a determinant of activity, the activity order within each isomeric series being usually 2-pyridyl greater than 3- and 4-pyridyl. There was no significant difference in activity between otherwise similar compounds derived from 2-cyano-1,1-iminodiamine (7, X = NCN) or 2-nitro-1,1-ethenediamine (7, X = CHNO2). All compounds had a substituent (R) attached to the C-4 position of the dihydropyridine ring, and the nature of the R substituent influenced the H2-antagonist activity, the relative activity order being usually n-Bu greater than Ph greater than Me. In general, the incorporation of the terminal nitrogen into a 1,4-dihydropyridyl ring system favoured biological activity, 1-(2-[(4-Pyridylmethylthio)ethylamino])-1-(1-[3-(4, 4-dimethyloxazolin-2-yl)-4-n-butyl-1,4-dihydropyridyl)-2- cyanoimine (7f) was the most potent H2-receptor antagonist exhibiting an activity approaching that of cimetidine.

Enhanced delivery and sustained release of estradiol (E2) in the brain could have potential clinical applications in the effective treatment of vasomotor "hot flushes" and prostatic cancer. We have, therefore, evaluated a brain-enhanced E2-chemical delivery system (E2-CDS), which is based upon the interconvertible dihydropyridine in equilibrium with pyridinium salt redox reaction. In this study, we evaluated the tissue distributions of E2-Q+ and E2--the inactive and active metabolites of the E2-CDS. Both E2-Q+ and E2 were detected in all tissues analyzed. In peripheral tissues, E2-Q+ and E2 were rapidly cleared, but in brain, concentrations of both compounds exhibited a slow decline with a t1/2 = 8 days. 14 Days after the E2-CDS administration, brain levels of E2-Q+ exceeded plasma levels by 170-fold, fat levels by 20-fold, and liver levels by 8-fold. Similarly, brain-E2 levels exceeded plasma levels by 38-fold, fat levels by 11-fold, and liver levels by 7-fold. Furthermore, levels of E2-Q+ In anterior pituitary, kidney, heart, and lung were initially 2- to 6-fold higher than brain levels, but 14 days after the E2-CDS administration, brain levels of E2-Q+ exceeded E2-Q+ levels in these peripheral tissues by 1.5- to 3-fold. The increased brain/peripheral tissues ratios of E2-Q+ and E2 in rats treated with the E2-CDS support brain-enhanced delivery and sustained release of E2 from this delivery system.

In this review, phosphoinositide metabolism is discussed and potential sites for therapeutic intervention are identified. The rapid recent progress in several branches of inositol chemistry has greatly improved our knowledge of the structural requirements for recognition by a variety of key enzymes involved in the pathways, and by the physiological receptor for D-myo-inositol 1,4,5-trisphosphate. Based on existing leads, drug opportunities arise in reducing polarity, in the utilisation of apolar pro-drugs, and in the development of innovative intracellular delivery systems. The identification of novel pharmacophores for future exploration is likely.

Transdermal delivery systems were prepared and evaluated for their ability to co-deliver the contraceptive agent levonorgestrel and the penetration enhancer ethyl acetate across hairless guinea pig, hairless mouse, and rat skin. The 24 hr devices were prepared with membranes composed of ethylene vinyl acetate [EVAc, 7.5% vinyl acetate (VAc) content] copolymers, and blends of EVAc (7.5% VAc content) and poly(methyl methacrylate) or poly(ethyl methacrylate). The reservoir phase (levonorgestrel-saturated ethyl acetate gelled with 2 wt% hydroxypropyl cellulose) was also evaluated for drug and solvent delivery with each of the rodent skins. Devices were also tested in which levonorgestrel was suspended in the adhesive. The results indicate that all the devices deliver levonorgestrel and the enhancer at about the same rate regardless of the skin type. It appears that the flux of LN follows the flux of EtAc until the devices are nearly depleted of EtAc, when delivery of LN remains relatively high.

The in vitro antidopamine activity of substituted N-[(1-alkyl-2-pyrrolidinyl)methyl]-6-methoxysalicylamides was found to be well correlated with the hydrophobic and electronic nature of substituents at the 3-position, and with the steric nature of groups replacing the hydrogen atom of the salicyl hydroxy group. In contrast, only the hydrophobic and steric characteristics were found to be important in the in vivo activity of these neuroleptics. This difference suggests that different mechanisms are probably involved in their in vitro and in vivo actions, and that the relevant receptors are slightly different in structure. The in vitro results suggest that electron donation by the 3-substituent strengthens the formation of a hydrogen bond between the carbonyl group of the amide moiety and a hydrogen of the receptor.