Serotonin/dopamine receptor antagonists

Bever KA, Perry PJ. Olanzapine a serotonin-dopamine-receptor antagonist for antipsychotic therapy. Am J Health Syst Pharm 1998 55(10) 1003-16. 

Ponzoni, A., Monti, J. M., Jantos, H., Altier, H. Monti, D. (1995). Increased waking after intra-accumbens injection of m-chlorophenylbiguanide prevention with serotonin or dopamine receptor antagonists. Eur. J. Pharmacol. 278, 111-15. 

Listing of antidepressants grouped by principal mechanism of action in the synapse. Abbreviations MAOI—irreversible = irreversible monoamine oxidase inhibitor MAOI—reversible = reversible monoamine oxidase inhibitor NDRl = norepinephrine/ dopamine reuptake inhibitor NRI = norepinephrine reuptake inhibitor NSRl = norepinephrine/serotonin reuptake inhibitor NSSA = norepinephrine/specific serotonin agonist SRI = serotonin reuptake inhibitor SRl/serotonin-2 blocker = serotonin reuptake inhibitor and serotonin-2 receptor antagonist. 

The large majority of antipsychotic drugs act mainly as dopamine receptor antagonists reducing the excess responsiveness to that neurotransmitter present in psychoses. It was found a decade ago that antagonists of serotonin H2 showed promising antipsychotic activity in several model systems. These dmgs would be better tolerated than their predecessor since they should be devoid of side effects... 

Metoclopramide (Reglan, and others) is both a serotonin- and dopamine-receptor antagonist. Given alone, it is less effective than TV ondansetron. Given concurrently with dexamethasone and either the antianxiety agent lorazepam (Ativan, and others) or the antihistamine diphenhydramine (Benadryl, and others), it can control emesis due to high-dose cisplatin (120 mg/m2) in older adults. One study in older patients, however, found metoclopramide, dexamethasone, and diphenhydramine less effective than IV ondansetron combined with dexamethasone in patients taking > 50 mg/m2... 

Drugs that potentiate the function of serotonin, such as venlafaxine, can produce pharmacodynamic interactions with dopamine receptor antagonists, perhaps because serotonin pathways can inhibit dopamine neurotransmission. 

Abadi, A. H., Lankow, S., Hoefgen, B., Decker, M., Kassack, M. U., Lehmann, J. Dopamine/serotonin receptor ligands, part 111 synthesis and biological activities of 7, 7 -alkylene-te-6, 7, 8, 9, 14, 15-hexahydro-5H-benz[d]indolo[2, 3-g]azednes — application of the bivalent ligand approach to a novel type of dopamine receptor antagonist. Arch. Pharm. (Weinheim) 2002, 335, 367—373. 

Ondansetron is not a dopamine-receptor antagonist. Becanse serotonin receptors of the 5-HT3 type are present both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone, it is not certain if ondansetron s antiemetic action is mediated centrally, peripherally, or in both sites (see Fignre 73). 

Lanzac LY170053 Olansek Olanzapine Zyprexa. A serotonin and dopamine receptor antagonist with anticholinergic activity a tricyclic antipsychotic. Antipsychotic. Crystals mp = 195°. // Lilly Co. 

Haloperidol, a dopamine receptor antagonist, was cytotoxic to mouse clonal hippocampal HT22 cells in a concentration-dependent manner and caused death by oxidative stress as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazo-lium bromide (Post et al. 1998). The addition of haloperidol to HT22 cells led to an increase in intracellular peroxides and a rime-dependent drop in the intracellular glutathione levels. Haloperidol-induced oxidative cell death was prevented by melatonin, its precursor N-acetyl serotonin, and most effectively by a-tocopherol. 

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... 

Antipsychotics (conventional agents have nonspecific dopamine receptor antagonsim atypical agents also have serotonin antagonist activity), ecopipam, GBR-12909 and other partial dopamine agonists (may be functional antagonists)... 

Opioids, benzodiazepines, barbiturates, corticosteroids, dopamine agonists (e.g., amantadine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole), H2-receptor antagonists, anticholinergics (e.g., diphenhydramine, trihexylphenidyl), P-adrenergic blockers, clonidine, methyldopa, carbamazepine, phenytoin, baclofen, cyclobenzaprine, lithium, antidepressants (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors), and interleukin-2... 

Figure 3 Putative model for the mechanism by which biogenic amines stimulate CE secretion across the rabbit corneal epithelium. Epn = epinephrine Nep = norepinephrine Tim = Timolol Ser = serotonin Msg = methysergide Dop = dopamine Hal = haloperi-dol (E = (E-adrenoceptor AC = adenylate cyclase. The scheme is consistent with the observation that epithelial responsiveness to serotonin and dopamine can be blocked by their receptor antagonists haloperidol and methysergide, respectively, and by both timolol treatment and sympathectomy. The probable source of serotonin or dopamine is the sympathetic fibers that innervate the cornea. (From Ref. 284.)...

Broening, H.W., Morford, L.L., Vorhees, C.V. Interactions of dopamine D, and D2 receptor antagonists with D-methamphetamine-induced hyperthermia and striatal dopamine and serotonin reductions. Synapse. 56 84, 2005. 

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