Agonists examples

The development of new drugs usually requires the synthesis of large numbers of structurally related compounds. If a set of agonists of this kind is tested on a particular tissue, the compounds are often found to fall into two categories. Some can elicit a maximal tissue response and are described as full agonists in that experimental situation. Others cannot elicit this maximal response, no matter how high their concentration, and are termed partial agonists. Examples include ... 

Reversible agonists (activators), i.e. the drug mimics the physiological agonist. Example Isoproterenol, an agonist at (3-adrenergic receptors. 

Another type of anxiolytic is buspirone, which appears to work principally as a partial agonist at 5-HTia receptors (see 5-HYDROXYTRYPTAMINE receptor agonists). Examples under development include tandospirone, zalospirone and zolmitriptan. 

Hydroxylated 2-aminotetralins are potent dopamine receptor agonists. Examples of such are 5-hydroxy-2-(N,N-di- -propylamino)tetralin (5-OH-DPAT, 9)98,100,205 and 7-hydroxy-2-(N,N-di-w-propylamino)tetralin (7-OH-DPAT, 10) 79,213 These compounds have no clinical utility because of their low oral bioavailability and their short duration of action, due to glucuronidation in the liver and gut.161 We have synthesised and tested 6-(N,N-di-//-propyl)amino-4,5,6,7-tetrahydrobenzo[ ]thiophene (34) and 5-(N,N-di-/ -propyl )ami no-4,5,6,7-tetrahydrobenzo[/i]thiophene (35), which are thiophene analogues of hydroxylated 2-aminotetralins. These tetrahydrobenzo[/)]thiophenes turned out to possess a higher relative oral bioavailability than 5-OH-DPAT (chapter 4 and ref. 215). However, the affinity for the dopamine receptors is diminished, as compared to 5-OH-DPAT (chapter 2, ref. 239). 

Two fundamental questions have emerged from these studies, ie, to what extent are agonists and antagonists binding similarly or differendy to the respective receptors, and can inhibitory compounds be developed that are active in vivo in humans as well as in vitro. An oxytocia antagonist that can block premature uterine contractions presents a promising example of the clinical utihty of such stmctures (47). Both linear as well as bicycHc modifications of these hormones also have provided new antagonist stmctures. 

Future Outlook for Antidepressants. Third-generation antidepressants are expected to combine superior efficacy and improved safety, but are unlikely to reduce the onset of therapeutic action in depressed patients (179). Many dmgs in clinical development as antidepressive agents focus on estabhshed properties such as inhibition of serotonin, dopamine, and/or noradrenaline reuptake, agonistic or antagonistic action at various serotonin receptor subtypes, presynaptic tt2-adrenoceptor antagonism, or specific monoamine—oxidase type A inhibition. Examples include buspirone (3) (only... 

Besides behavior and blood pressure, catecholamine neurons also have important roles in other brain functions. Regulation of neuroendocrine function is a well-known action of catecholamines for example, DA agonists reduce semm prolactin concentration, especially in conditions of hypersecretion. Ingestive behavior can be modulated by brain catecholamines, and some appetite-suppressing dmgs are beheved to act via catecholaminergic influences. Catecholamines also participate in regulation of body temperature. 

Protein engineering is now routinely used to modify protein molecules either via site-directed mutagenesis or by combinatorial methods. Factors that are Important for the stability of proteins have been studied, such as stabilization of a helices and reducing the number of conformations in the unfolded state. Combinatorial methods produce a large number of random mutants from which those with the desired properties are selected in vitro using phage display. Specific enzyme inhibitors, increased enzymatic activity and agonists of receptor molecules are examples of successful use of this method. 

Recently, two examples of the separation of enantiomers using CCC have been published (Fig. 1-2). The complete enantiomeric separation of commercial d,l-kynurenine (2) with bovine serum albumin (BSA) as a chiral selector in an aqueous-aqueous polymer phase system was achieved within 3.5 h [128]. Moreover, the chiral resolution of 100 mg of an estrogen receptor partial agonist (7-DMO, 3) was performed using a sulfated (3-cyclodextrin [129, 130], while previous attempts with unsubstituted cyclodextrin were not successful [124]. The same authors described the partial resolution of a glucose-6-phosphatase inhibitor (4) with a Whelk-0 derivative as chiral selector (5) [129]. 

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