Inhibition, pharmacological

Angiotensin II causes vasoconstriction by direct stimulation of ATj receptors on the vascular smooth muscle. It also enhances release of the neurotransmitter norepinephrine from the sympathetic nerve fibers present in the blood vessels. The vasopressor effects of Ag II may be inhibited pharmacologically in order to decrease TPR and treat hypertension. An important class of orally active drugs is the ACE inhibitors, including captopril and enalopril, which prevent formation of Ag II. More recently, angiotensin receptor antagonists have been developed that act at the vascular smooth muscle. These drugs, which include losartin and valsartan, are also orally active. 

Singh A, Naidu PS, Kulkarni SK, Quercetin potentiates L-DOPA reversal of drug-induced catalepsy in rats, possible COMT/MAO inhibition. Pharmacology 68 81-88,2003. 

Another class of endoprotease inhibitors was developed that contained a-chloro ketones as the chemical warhead [22]. BFCCMK (Figure 9.1), a simple prenylcysteine analog, presumably operates by an active-site residue displacing the reactive a-chloro ketone. The potency of BFCCMK over nonlipidic small molecules further demonstrates that there are necessary and specific lipophilic motifs for Reel binding and inhibition. Pharmacologic... 

Fluorouracil and relative drugs, metabolism, mechanism of RNA and DNA synthesis inhibition, pharmacology of 87PHA73. 

Protamine sulfate is used. This molecule is highly charged and binds tightly to the heparin molecule, thus inhibiting pharmacological action. 

Pride, E., Barg, J., Levy, R., Saya, D., Heldman, E., Mechoulam, R., and Vogel, Z. (1995) Low doses of anandamides inhibit pharmacological effects of A -tetrahydrocannabinol, Journal of Pharmacology and Experimental Therapeutics 272 699-707. 

Very low doses of anandamide and the synthetic endocannabinoid-like docosa-hexaenylethanolamide, but not of A -tetrahydrocannabinol (THC), inhibited pharmacological effects of conventional doses of A -THC (27). 

Biologica.1 Activities a.ndAna.logues, The many pharmacological actions of neurotensin include hypotension, increased vascular permeabihty, hyperglycemia, increased intestinal motility, and inhibition of gastric acid secretion (120). In the brain, it produces analgesia at remarkably low doses (121). 

In addition, vinpocetine selectively inhibits a specific calcium, calmodulin-dependent cycHc nucleotide phosphodiesterase (PDF) isozyme (16). As a result of this inhibition, cycHc guanosine 5 -monophosphate (GMP) levels increase. Relaxation of smooth muscle seems to be dependent on the activation of cychc GMP-dependent protein kinase (17), thus this property may account for the vasodilator activity of vinpocetine. A review of the pharmacology of vinpocetine is available (18). 

Opiates iateract with three principal classes of opioid GPCRs )J.-selective for the endorphiQS,5-selective for enkephalins, and K-selective for dynorphias (51). AU. three receptors have been cloned. Each inhibits adenylate cyclase, can activate potassium channels, and inhibit A/-type calcium channels. The classical opiates, morphine and its antagonists naloxone (144) and naltrexone (145), have moderate selectivity for the. -receptor. Pharmacological evidence suggests that there are two subtypes of the. -receptor and three subtypes each of the 5- and K-receptor. An s-opiate receptor may also exist. 

The therapeutic efficacy of a dmg is generally measured in terms of ED q or ID q which represent the concentration of dmg which produces 50% of the maximum effect or 50% of maximum inhibition. LD q represents the concentration of dmg that produces 50% fataUties in test animals. The therapeutic index is the ratio of the ED q versus LD q. Detailed descriptions of the terminology and fundamental principles of pharmacology are available (32) (see Pharmacodynamics). 

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. 

Oxolamine [959-14-8] (57) is sold in Europe. It is an oxadiazole, and its general pharmacological profile is described (81). The compound possesses analgesic, antiinflammatory, local anesthetic, and antispasmodic properties, in addition to its antitussive activity. Although a central mechanism may account for some of the activity, peripheral inhibition of the cough reflex may be the dominant effect. The compound has been shown to be clinically effective, although it is less active than codeine (82,83). The synthesis of oxolamine is described (84). 

As regards toxicity, pyrazole itself induced hyperplasia of the thyroid, hepatomegaly, atrophy of the testis, anemia and bone marrow depression in rats and mice (72E1198). The 4-methyl derivative is well tolerated and may be more useful than pyrazole for pharmacological and metabolic studies of inhibition of ethanol metabolism. It has been shown (79MI40404) that administration of pyrazole or ethanol to rats had only moderate effects on the liver, but combined treatment resulted in severe hepatotoxic effects with liver necrosis. The fact that pyrazole strongly intensified the toxic effects of ethanol is due to inhibition of the enzymes involved in alcohol oxidation (Section 4.04.4.1.1). 

Thiirane is more bactericidal than oxirane, and derivatives of 2-mei captomethylthiirane inhibit tuberculosis. The following pharmacological uses have been reported for compounds derived from thiirane derivatives gold complexes of the adducts of diethylphosphine and thiirane (antiarthritic), adducts of thiiranes and malononitrile (antibacterial, blood vessel dilators, muscle relaxants, sedatives), thermolysis products of thiirane 1-oxides and adducts of thiirane 1-oxides with sulfenyl chlorides (antibacterial), adducts of 2,3-diarylthiirene 1,1-dioxides with ynamines (antibacterial, parasiticidal), adducts of 2,3-diarylthiirene 1,1-dioxides with enamines (antifertility), adducts of p-aminophenylacetic esters with thiirane (immunosuppressants), adducts of amines and thiiranes (radioprotective drugs). 

According to Nyman the pharmacological action of hyoscine is considerably modified in the quaternary compounds of the alkaloid, e.g., the inhibiting action on salivary secretion is greatly increased in the methonitrate, as is also the spasmolytic activity, but the mydriatic action is unchanged and the central sedative activity disappears. 

Pharmacological Action. As already pointed out, cularine shows some resemblance to papaverine and hydrastine in action (p. 196). The M.L.D. (mgm./kilo.) for mice by intravenous injection of ochotensine is 10-6 i 0-54 so that it seems to be the most toxic of the fifteen corydalis alkaloids examined by Anderson and Chen, who also state that it stimulates isolated guinea-pig or rabbit uterus, inhibits isolated rabbit-intestine and induces a fall in blood pressure on intravenous injection in etherised cats. 

Umbellatine was examined by Gupta and Kahali, who found that it killed Paramoecium at 1 in 500 and Leishmania tropica at 1 in 50,000, but did not inhibit L. donovani or Entamoeba histolytica at 1 in 10,000. It remembles berberine in the nature and range of its pharmacological activity but is more active in producing cardiovascular response and is possibly more potent in the treatment of oriental sore. 

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