Autoreceptors antagonists

Serotonin (5-HT)-tenninal autoreceptor antagonists, 41 (2003) 129 Single photon emission tomography (SPET), 38 (2001) 189... 

Olive M. F., Seidel W. F., Edgar D. M. (1998). Compensatory sleep responses to wakefulness induced by the dopamine autoreceptor antagonist (-(DS121. J. Pharmacol. Exp. 7her. 285(3), 1073-83. 

Svensson, K. (1986) Thesis Dopamine autoreceptor antagonists A new class of central stimulants. University ofGoteborg, Gdteborg, Sweden, ISBN 91-7900-078-9. Nedelec, L., Guillaume, J. and Dumont, C. (1976) Fr. Patent 76-3933 (1977) Chem. Abstr. 87, 152038. 

Although postsynaptic DA agonists and presynaptic Dj autoreceptor antagonists share a common property of enhancing DA transmission, Dj autoreceptor agonists have been developed specifically to block DA transmission as an alternative approach to antipsychotic therapy (Benkert et al. 1992). A variety of such compounds are available (Seyfried and Boettcher 1990), four of which—talipexole, pramipexole, roxindole, and OPC-4392 —have been evaluated as antipsychotics in schizophrenic patients (Benkert et al. 1992). Only roxindole has been tested in depression, and then only in two uncontrolled pilot studies over 4 weeks of treatment (Benkert et al. 1992 M. Kellner et al. 1994). Response rates similar to those of imipramine were observed, with a fast onset of action in some patients. Roxindole s antidepressant action may lie in its ability to selectively stimulate supersensitive postsynaptic Dj receptors, and thereby enhance DA function, or in its additional properties as an inhibitor of serotonin reuptake and as a 5-HT, receptor agonist (Benkert et al. 1992 Seyfried et al. 1989). 

Dopamine - low doses of the dopamine agonist apomorphine increase slow-wave sleep and, like other dopaminometics, cause somnolence in patients with Parkinson s disease. Conversely, dopamine autoreceptor antagonists, which enhance dopamine release, reduce both REM and non-REM sleep. Stimulants such as cocaine cause arousal by activating D2 postsynaptic receptors, effects which are blocked by most neuroleptics. 

Roberts C, Price GW. Interaction of serotonin autoreceptor antagonists in the rat dorsal raphe nucleus an in vitro fast cyclic voltammetry study. Neurosci Lett 2001 300 45-48. 

Onali P, Olianas MC, Bunse B (1988) Evidence that adenosine A2 and dopamine autoreceptors antagonistically regulate tyrosine hydroxylase activity in rat striatal synaptosomes. Brain Res 456 302-309. 

Interestingly, it appears that fluoxetine is now being successfully used to treat some patients suffering from anxiety. The mechanism of action of this effect is unclear. It could be that an autoreceptor antagonist could mimic this effect or it may be that fluoxetine treatment is causing down regulation of a postsynaptic receptor. Whichever is the case, the possible role(s) of 5-HT,e and 5-HTip receptors in anxiety should also be investigated. 

The Hs receptor modulates the release and synthesis of histamine as a presynaptic autoreceptor. Antagonists/inverse agonists of the H3 receptor have been suggested to have potential as drug therapies for various central nervous system (CNS) disorders. A/-methyl-A/-(2-piperidin-1-ylethyl)-4-(2-naphthyl)piperidine-1-carboxamide (1) was identified as a lead compound, which had an IC50 value of 110 nM for the human H3 receptor (hH3) upon screening of Merck sample collections. After the modification of the left hand moiety of 1, frans-A/-methyl-A/-(2-piperidin-1-ylethyl)-3/-/-spiro[3-oxo-2-benzofuran-1, T-cyclohexane]-4 -carboxamide (2) was identified as a markedly potent analogue. 

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