Activity pharmacological

The appearance of the 2-(indol-3yl)ethylamine (tryptamine) unit in both tryptophan-derived natural products and in synthetic materials having potential pharmacological activity has generated a great deal of interest in the synthesis of such compounds. Several procedures which involve either direct 3-alkylation or tandem 3-functionalization/modification have been developed. Similarly, methodology applicable to preparation of tryptophan analogues has been widely explored. 

Yohimbine (104), also from the bark of C.johimbe K Schum. and from the roots of R. serpentina (1. ) Benth. has a folk history (unsubstantiated) of use as an aphrodisiac. Its use has been confirmed experimentally as a local anesthetic, with occasional employment for rehef ia angiaa pectoris and arteriosclerosis, but is frequently contraindicated by its undesired renal effects. Yohimbine and some of its derivatives have been reported as hahuciaogenic (70). In addition, its pattern of pharmacological activities ia a variety of animal models is so broad that its general use is avoided. All ten carbon atoms of secologanin (102) as well as the entire skeleton of tryptamine (98, R = H) are clearly seen as iatact portions of this alkaloid. 

Several biologically and pharmacologically active compounds have been prepared from the condensation of the acid chloride of 1-naphthoxyacetic acid with carbazole, iadole, or pyrrole ia 2A[ NaOH solution ia ethanol (63). Also, naphthyloxy derivatives of imidazole, benzimidazole, and benzotriazoles have been synthesized and screened for their antimicrobial, analgesic, and antiinflammatory activities. 2-Naphthyloxy derivatives are comparatively more active than 1-naphthyloxy derivatives (64). 

The therapeutically active dmg can be extracted from plant or animal tissue, or be a product of fermentation (qv), as in the case of antibiotics. Frequentiy, it is synthesized and designed to correlate stmcture with therapeutic activity. Pharmacologic activity is first tested on laboratory animals. When the results ate encouraging, physical and chemical properties are determined in the so-called preformulation stage, and analytical procedures are developed for quahty control (see Qualityassurance/qualitycontrol). 

The issue of dmg stereoselectivity has become one of both developmental and regulatory significance. In principle, a racemic dmg possesses only 50% of the active ingredient, and the rest may have other or interacting pharmacologic activities, which may contribute a metaboHc burden or be inert. 

Increasing attention has been paid to the generation of quantitative stmcture—activity relationships in which the effects of molecular substitution on pharmacologic activity can be interpreted in terms of the physicochemical properties of the substituents. These approaches are based on the extrathermodynamic analysis of substituent effects (36) ... 

The PGs, PGI2 and TXA2 collectively exhibit a wide variety of biochemical and pharmacological activities and are iavolved ia both physiological and pathophysiological processes. However, the iadividual compounds show different overall activity profiles sometimes ia opposiag directions. Excellent reviews are available (59—64). A survey of some of the more important biological actions of the prostanoids foUow. 

Various borate esters are chemostetilants for house flies (51). Tributyl borate, available from Eagle-Picher, Miami, Oklahoma, which is isotopically enriched in boron-10, is being used as a chemical precursor in the synthesis of pharmacologically active boron compounds suitable for boron neutron capture therapy. 

This carboxyborane can undergo an amine exchange reaction with Hquid ammonia (eq. 7) to yield the boron analogue of glycine, the simplest alpha-amino acid (13). There has been a great deal of work on the pharmacological activity of these amino acid analogues (14). 

Because digitoxin is a nonpolar, lipophilic glycoside, absorption from the GI tract is complete. About 90% of the dmg in plasma is tightly bound to protein. It is metabolized in the Hver to many metaboHtes, including digoxin which is the only pharmacologically active metaboHte. The dmg is excreted via the bile into feces. The elimination half-life of digitoxin is seven to nine days (87). 

Isosorbide is rapidly absorbed and undergoes rapid first-pass metaboHsm by the Hver. The bioavaUabUity of the subHngual and chewable tablets is 59% and 22%, respectively, for the regular tablet. Isosorbide is metabolized to isosorbide-2-mononitrate and isosorbide-5-mononitrate, both of which have pharmacologic activity. The elimination half-Hves of subHngual and po isosorbide dinitrate ate 1 and 4 h, respectively. Those of the 2- and 5-mononitrate metaboHtes are 1.5—3.1 h and 4—5.6 h, respectively. The two metaboHtes prolong the elimination half-life of the dinitrate. Adverse effects with isosorbide are similar to those described for nitroglycerin (99). 

Nicardipine is almost completely absorbed after po adrninistration. Administration of food decreases absorption. It undergoes extensive first-pass metaboHsm in the Hver. Systemic availabiHty is dose-dependent because of saturation of hepatic metaboHc pathways. A 30 mg dose is - 35% bioavailable. Nicardipine is highly protein bound (>95%). Peak plasma concentrations are achieved in 0.5—2.0 h. The principal path of elimination is by hepatic metaboHsm by hydrolysis and oxidation. The metaboHtes are relatively inactive and exert no pharmacological activity. The elimination half-life is 8.6 h. About 60% of the dose is excreted in the urine as metaboHtes (<1% as intact dmg) and 35% as metaboHtes in the feces (1,2,98,99). 

Absorption after po dosing is fairly complete. It undergoes extensive first-pass metaboHsm in the Hver and is 60% bioavailable. It is extensively bound (99%) to a -acid glycoproteins. Bepridil is almost completely metaboli2ed in the Hver. Seventeen metaboHtes have been identified but only the 4-hydroxy-A/-phenyl-bepridil has some pharmacological activity. The elimination half-life is 33—42 h (107). 

Two important pathways for catecholamine metaboHsm are 0-methylation by COMT, which is cytoplasmicaHy localized, and oxidative deamination by the mitochondrial localized enzyme MAO. There are large amounts of MAO in tissues such as the fiver and the heart which are responsible for the removal of most of the circulating monoamine, including some taken in from the diet. Tyramine is found in high concentrations in certain foods such as cheese, and in wine. Normally, this tyramine is deaminated in the fiver. However, if MAO is inhibited, the tyramine may then be converted into octopamine [104-14-37] which may indirecdy cause release of NE from nerve terminals to cause hypertensive crisis. Thus MAO, which is relatively nonspecific, plays an important role in the detoxification of pharmacologically active amines ingested from the diet. 

Most of the pharmacologically active indazole derivatives are useful as antiinflammatory drugs, e.g. bendazac or [(1-benzyl-l J/-indazol-3-yl)oxy]acetic acid (LDso in mice and rats of 355 and 388mgkg i.p., respectively) and benzydamine or l-benzyl-3-[3-(dimethyl-amino)propoxy]-l//-indazole (LDso in mice and rats of 110 and lOOmgkg" i.p., respectively). The last cited compound also has analgesic and antipyretic properties (B-76MI40404). 

Drugs and other chemicals such as food additives or insecticides foreign to the body undergo enzymatic transformations that result in loss of pharmacological activity detoxification), or lead to the formation of metabolites with therapeutic or toxic effects bioactivation). 

A number of azetidines have been investigated for pharmacological activity, but no important derivatives have emerged (64HC(19-2)908, 68JMC466, 69JMC196, 79JMC183). 

Dibenzo[b,/]thiepin, 10,11 -dihydroapplications, 7, 591 pharmacological activity, 7, 591 Dibenzothiepins synthesis, 7, 588 Dibenzo[6,/ thiepins applications, 7, 592 synthesis. 7. 587... 

Imidazolidin-2-one, l-(5-nitro-2-thiazolyl)-pharmacological activity, 6, 328 Imidazolidin-4-one, l-aryl-3-phenyl-2-thioxo- C NM S, 355 Imidazolidinones C NMR, 5, 355 Imidazolidin-2-ones nucleophilic displacement, 5, 428 polymers, 1, 279-280 reactivity, 5, 376 synthesis, 5, 466, 471 Imidazolidin-4-ones synthesis, 5, 468 Imidazoline, 2-alkyl-synthesis, 5, 463 Imidazoline, 2-amino-applications, 5, 498 Imidazoline, 2-aryl-synthesis, 5, 463 Imidazoline, 2-methyl-synthesis, 5, 487 Imidazoline, 2-nitroamino-synthesis, 5, 471 2-Imidazoline, 2-arylamino-tautomerism, 5, 368 2-Imidazoline, 1-benzyl-methylation, 5, 425 2-Imidazoline, 1,2-diaryl-synthesis, 5, 463... 

Pteridine, 2,4,7-triamino-6-phenyl-pharmacological activity, 3, 325 Pteridine, 2,4,6-trichloro-properties, 3, 267 Pteridine, 2,4,7-trichloro-properties, 3, 267 reaction, 3, 291 Pteridine, 4,6,7-trichloro-reaction, 3, 291 Pteridine, 4-trifluoromethyl-structure, 3, 266 Pteridine, 2,6,7-trimethyl-structure, 3, 266 Pteridine, 4,6,7-trimethyl-NMR, 3, 266... 

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