Receptors of mediators

The vast majority of drugs produce their effects by interacting with proteins, either with those on the surface of the cell comprising the plasma membrane, such as receptors of mediators, ionic channels and transporters (about 60% of drugs), or with components of the interior of the cell, such as enzymes and nuclear receptors. 

Receptors of mediators are able to interact with a large diversity of ligand types (Figure 4.1) ... 

Receptors of mediators inclnding an intrinsic ion channels (ligand-gated ion channels snch as nicotinic receptors), or an enzyme activity (i.e. a tyrosine kinase activity such as insnlin receptors, or ganylyl cyclase activity such as ANF receptors) have ligands for their receptor part (agonists and antagonists) as well as for their ion channel (openers and inhibitors or blockers) or enzyme part (inhibitors). 

Anti-inflammatory compounds can act at different levels. They can, for example, decrease vasodilatation and edema, as in the case of antihistaminic drugs inhibit PGs synthesis as do the non-steroidal antiinflammatory drugs modify synthesis or block the receptors of mediators such as PAF or LTs interfere with the functions of peptide mediators block the transcription factors or scavenge free radicals generated in the process. Natural products as anti-inflammatory agents may act at different levels, some by non specific pathways as antioxidants do or by a specific mechanism via receptor antagonism. The lignans can act in both cases. 

The ability of receptors to couple to G-proteins and initiate GTPase activity may also be independent of ligand. Thus, specific mutations in a- and P-adrenergic receptors have led to receptors that mediate agonist-independent activation of adenylyl cyclase (69,70). These mutations presumably mimic the conformational state of the ligand-activated receptor when they are activated conventionally by ligands. 

Biochemically, most quaternary ammonium compounds function as receptor-specific mediators. Because of their hydrophilic nature, small molecule quaternaries caimot penetrate the alkyl region of bdayer membranes and must activate receptors located at the cell surface. Quaternary ammonium compounds also function biochemically as messengers, which are generated at the inner surface of a plasma membrane or in a cytoplasm in response to a signal. They may also be transferred through the membrane by an active transport system. 

Beta receptors of the beta-1 subtype mediate an increase in heart rate and increased force of contraction they are also found in the central nervous system. E and NE are equaHy potent agonists and selective antagonists are atenolol [29122-68-7] and betaxolol [63659-18-7]. Beta-2 receptors are weH known for their involvement in relaxing bronchioles. E is a more potent agonist than NE procaterol [72332-33-3] is a selective agonist ICl 118551 and a-methylpropranolol are selective antagonists. A particular amine may act on both alpha and beta receptors or predominandy on one type. NE acts mainly on alpha-1, E on both alpha and beta, and isoprotemol [7683-59-2] almost exclusively on beta receptors. Numerous antagonists also differentiate between... 

Adenosine is produced by many tissues, mainly as a byproduct of ATP breakdown. It is released from neurons, glia and other cells, possibly through the operation of the membrane transport system. Its rate of production varies with the functional state of the tissue and it may play a role as an autocrine or paracrine mediator (e.g. controlling blood flow). The uptake of adenosine is blocked by dipyridamole, which has vasodilatory effects. The effects of adenosine are mediated by a group of G protein-coupled receptors (the Gi/o-coupled Ai- and A3 receptors, and the Gs-coupled A2a-/A2B receptors). Ai receptors can mediate vasoconstriction, block of cardiac atrioventricular conduction and reduction of force of contraction, bronchoconstriction, and inhibition of neurotransmitter release. A2 receptors mediate vasodilatation and are involved in the stimulation of nociceptive afferent neurons. A3 receptors mediate the release of mediators from mast cells. Methylxanthines (e.g. caffeine) function as antagonists of Ai and A2 receptors. Adenosine itself is used to terminate supraventricular tachycardia by intravenous bolus injection. 

Antagonists of muscarinic acetylcholine receptors had widely been used since 1860 for the treatment of Parkinson s disease, prior to the discovery of l-DOPA. They block receptors that mediate the response to striatal cholinergic interneurons. The antiparkinsonian effects of drugs like benzatropine, trihexyphenidyl and biper-iden are moderate the resting tremor may sometimes respond in a favorable manner. The adverse effects, e.g., constipation, urinary retention, and mental confusion, may be troublesome, especially in the elderly. 

Benzodiazepines. Figure 3 Dissection of benzodiazepine pharmacology. The functional roles of GABAa receptor subtypes, mediating particular actions of diazepam, are indicated. A sign indicates that the respective response is mediated by the respective receptor subtype, a sign indicates that the respective response is apparently not mediated by the respective receptor subtype. ND = not determined. 

Edg Receptors central nervous system terminals of these neurons. Capsaicin-induced release of mediators is fundamentally tetrodotoxin resistant despite being ner ve mediated. 

Edg receptors are a group of recently discovered G-protein coupled receptors, which mediate the action of lysophospholipids (sphingosine-1 -phosphate, lysophosphatidic acid). Tachykinins and their Receptors... 

Ly sophosphatidic acid (LPA) is the prototype of a group of bioactive lysophospholipids that act on specific G-protein-coupled receptors to mediate a wide variety of cellular functions. 

Semaphorins are secreted, membrane-associated or transmembrane proteins defined by the presence of a sema-phorin protein domain (Serna domain). In the mammalian system, more than 20 semaphorins have been identified which play important roles in a variety of tissues. The best characterized receptors for mediating semaphoiin effects are members of the neuropilin and plexin families of transmembrane proteins. Semaphoiin functions are best described in the regulation of neural development, angiogenesis, immunoregulation and cancer. 

In some cases, receptor inactivation, e.g., of the V2 vasopressin receptor, is mediated by agonist-induced enzymatic cleavage of the GPCR. This nonendocytic proteolysis is promoted by a plasma membrane-associated metalloprotease. Proteinase-activated receptors (PARs) such as the thrombin receptor also follow a distinctly different pathway. PARs require the enzymatic cleavage of their N terminus, and the newly generated N terminus activates the receptor. Once... 

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