A-antagonist

Fig. 9. Correlation between binding and pharmacologic affinities where the dashed lines correspond to the theoretical correlation of 1 1 for a series of muscarinic receptor (a) antagonists, (1)—(9) and (b) agonists, (10)—(19). Correlation for the antagonists is essentially 1 1, deviating markedly from that...

The first SRS-A antagonist, FPL-55712 (26) (149), was discovered before the stmctures of the leukotrienes were detemiined. Although this compound is relatively weak as an antagonist and suffers from a very short half-life in vivo, it played an important role both in leukotriene stmcture elucidation and as a model for later antagonists. In work stmcturaHy related to FPL-55712, LY-171883 was developed (27) (150). LY-171883 was evaluated in several clinical trials before development was stopped. Orally adrninistered, LY-171883 blocked slightly the response to aerosol LTD improved pulmonary function (FEV ) in mild asthmatics (151), decreased the sensitivity of asthmatics to cold air-induced bronchoconstriction (152), and significantly reduced the bronchoconstrictor response to inhaled antigen (153). However, in all these studies the beneficial effects were minimal. 

Pollock, M. S. Mistlberger, R. E. (2003). Rapid eye movement sleep induction by microinjection of the GABA-A antagonist bicuculline into the dorsal subcoeruleus area of the rat. Brain Res. 962, 68-77. 

Antidepressants, tricyclic Anticholinergic effects, a-antagonist effects... 

Non-peptidic tachykinine antagonists were converted to photoprobe ligands by Ward. First, a piperidine derivative, CP-99,994 (Glaxo) was appended with a diazirine photophore (6, Fig. 7) to study SP (NK1) receptors [74]. A similar modification on a neurokinin A antagonist, SR 48968 (Sanofi) produced a photoligand (5, Fig. 7) in order to investigate NK2 receptor proteins [75]. 

Wermuth, C. G., Bourguignon, J.-J., Schlewer, G Gies, J.-P., Schoenfelder, A., Melikian, A., et al. (1987) Synthesis and structure-activity relationships of a series of aminopyridazine derivatives of y-aminobutyric acid acting as selective GABA-A antagonists../. Med. Chem. 30, 239-249. 

Herbert and McNeil have shown that the appropriate 2-iodoindole can be carbonylated in the presence of primary and secondary amines to afford the corresponding 2-indolecarboxamides in 33-97% yield. Further application of this protocol leads to amide 319, which is a CCK-A antagonist (Lintitript) [420]. 

Pretreatment of rats with a-noradrenergic antagonists blocked the hypothermia induced by chlordecone (Cook et al. 1988b). It is possible that if similar effects are observed in humans, a -antagonists may be capable of blocking the hypothermia. 

Aizawa, H., Inoue, H., Matsumoto, K., Koto, H., Nakano, H., and Kara, N. (1996) Thromboxane A antagonist inhibits leukotriene D -induced smooth muscle contraction in guinea-pig lung parenchyma, but not in trachea. Prostaglandins Leukot. Essent. Fatty Acids. 55,437-440. 

B., Okun, I., and Castillo, R.S. Structure-activity relationships of N2-aryl-3-(isoxazolylsulfamoyl)-2-thiophenecarboxamides as selective endothelin receptor-A antagonists. 

Fig. 3.7 Replacement of amide with acetyl in a series of amidothio-phenesulfonamide en-dothelin-A antagonists to improve oral bioavailability [11].

TAS-108 (SR16234) is a novel and orally active steroidal compound with a proposed additional molecular mode-of-action that is different from that of SERMs such as tamoxifen and raloxifene [157]. TAS-108 is a full estrogen receptor-a antagonist, and it should also recruit co-activator transcriptional intermediary factor 2 to ER-j6, which may have a preventive effect on bone loss [157]. 

Antagonist X (competitive) has an affinity for Rb but not Ra. Thus, it specifically antagonizes agonist B. It does not antagonize agonist A. Antagonist Y acts on a receptor associated with the cellular translocation of calcium and inhibits the increase in intracellular free calcium. It will therefore antagonize the effects of both A and B, since they both ultimately depend on calcium movement to cause contraction. 

Prazosin and other a-antagonists bnd use in the management of benign prostatic obstruction, especially in patients who are not candidates for surgery. Blockade of a-adrenoceptors in the base of the bladder and in the prostate apparently reduces the symptoms of obstruction and the urinary urgency that occurs at night. 

B. The adrenoceptors that epinephrine acts on to affect heart rate, renin release, bronchiolar tone, and glycogenolysis are (3-receptors. Prazosin is an a-antagonist so would not antagonize epinephrine at those receptors. The radial smooth muscle in the iris has a-receptors that when activated, contract the radial muscle which dilates the pupil. This action is antagonized by prazosin. 

Silodosin (Kissel) 2004 a., antagonist Figure 8.80 BPH treatment agents. 

Cl-988 has been found to reduce the behavioral stress in marmosets exposed to a human threat [Hughes et al. 1990]. L-365,260 can antagonize the behavioral effects of exposition to the odor of a cat in rats and suppress the behavioral reaction of mice to the calls of an owl, an effect also found with LY 288513 (Hendrie and Dourish 1994]. Thus, evidence suggests an anxiolytic activity of CCK-B antagonists. The activity seems more evident in etho-logically based models of anxiety than in conflict-based tests and does not follow a linear dose-dependent relationship but rather a bell-curve one. Also, most studies point to a selectivity of CCK-B antagonists, but not CCK-A antagonists, for anxiolytic effects. 

As mentioned in section 4.3.3, there are two kinds of a receptor in brain and peripheral tissues. The crucial experiments have shown that brain tissue prelabeled with pH]NE will release neurotransmitter upon electrical stimulation or exposure to K+. The release is reduced by the a agonist clonidine (4.42) and stimulated by the a antagonist yohimbine (4.43). Since the adrenoreceptor involved in this latter experiment plays a vital role in modulating neurotransmitter release, it must be presynaptic and located on the nerve-ending membrane. A similar selectivity has also been shown by peripheral tissues (heart, uterus), leading to the distinction of aj (postsynaptic) and (presynaptic) adrenergic receptors. There are also presynaptic [3 receptors, which show a feedback regulation opposite to that of the ttj receptors that is, their excitation by a neurotransmitter increases NE release. 

Yohimbine (4.43) is an antagonist. Yohimbine, an indole alkaloid closely related to reserpine—an a antagonist—has been evaluated as a potential treatment for male erectile dysfunction. Naphazoline (4.46) and other a-agonist imidazoline compounds are nasal decongestants, used by inhalation to decrease swelling of the nasal mucosa. Overdependence on and overuse of these drugs can lead to rebound swelling. 

Alpha-adrenoceptor antagonists inhibit the activation of a adrenoceptors by catecholamines. In the cardiovascular system these receptors are mainly located on the surface of smooth muscle cells in the walls of arteries and veins. On activation, they mediate an increase in intracellular free calcium, which induces smooth muscle contraction. Inhibition by an a antagonist causes arterial or venous vasodilatation. The postsynaptic effect is mainly mediated by ol adrenoceptors whereas o2 adrenoceptors are found on the presynaptic membranes of the sympathetic neurones. Activation of o2-adreno-ceptors results in auto-inhibition of catecholamine release. 

Considerable evidence indicates that the hypotensive effect of clonidine is exerted at a adrenoceptors in the medulla of the brain. In animals, the hypotensive effect of clonidine is prevented by central administration of a antagonists. Clonidine reduces sympathetic and increases parasympathetic tone, resulting in blood pressure lowering and bradycardia. The reduction in pressure is accompanied by a decrease in circulating catecholamine levels. These observations suggest that clonidine sensitizes brain stem vasomotor centers to inhibition by baroreflexes. 

There is a slightly increased risk of infection (as with other biologic DMARDs), predominantly of the upper respiratory tract. Concomitant use with TNF-a antagonists is not recommended due to the increased incidence of serious infection with this combination. Infusion-related reactions and hypersensitivity reactions, including anaphylaxis, have been reported but are rare. Anti-abatacept antibody formation is infrequent (< 5%) and has no effect on clinical outcomes. The incidence of malignancies is similar to placebo with the exception of a possible increase in lymphomas. The role of abatacept in this increase is unknown. 

White, W. F., Zhao, D. (3R,4S)-3-[4-(4-Fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol a conformationally restricted analoque of the NR2B subtype-selective NMD A antagonist (1S,2S)-1-(4-hydroxyphenol)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol, J. Med. Chem. 1998, 41, 1172-1184. 

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