Multiple receptor types

There is also preliminary data that risperidone, an atypical antipsychotic that antagonizes multiple receptor types including dopamine receptors and serotonin receptors, may affect certain ERP components. A study of chronic risperidone delivery via subcutaneous implants reported increased P20 amplitude but no effects on the N40 component. Risperidone in this study was unable to block the amphetamine-induced decreases in the P20 component, but attenuated amphetamine-induced reduction of the N40 (Siegel et al., 2004). 

Tritiated affinity labels have been useful in receptor isolation and for determination of the molecular weights of solubilized receptors (see Refs. 86, 99 for reviews). These compounds can be used to irreversibly block one or more receptor type in tissues containing multiple receptor types, so that the remaining receptors c be studied in isolation. The covalent binding cf affinity labels can be used to study receptor-ligand interactions. Thus Liu-Chen and coworkers have characterized the binding of the affinity labels j3-funaltrexamine (j8-FNA) and SUPER-FIT to ju. and S receptors, respectively, by use of a combination of molecular biology approaches and protein isolation (see below). 

Binding affinity For potency and selectivity must use multiple receptor types and subtypes, membranes or cells or pure receptor. 

The current system terms prostanoid receptors P receptors, which is preceded by a letter to indicate the most potent natural prostanoid at that particular receptor (hence the receptor at which PGD, is the most potent natural agonist is called the DP receptor and so on). This system was based initially upon a rigorous quantitative comparison of the agonist potencies of each of the natural prostanoids in tissue preparations chosen to avoid the problems associated with multiple receptor types. In addition, being aware of the limitations of agonists in receptor classification (111), efforts were made to identify specific prostanoid-receptor antagonists. A summary of the current state of prostanoid receptor classification is shown in Table 6.2. 

Although thermodynamic parameters can be obtained for interaction mechanisms that are complex, interpretation of the results is greatly simplified when the interaction mechanism is simple. For example, tissues in which multiple receptor types are expressed will yield results different from tissues expressing only one type, unless a type-selective ligand is used. 

In radioligand binding studies, non-linear Scatchard plots or competition curves that have abnormally steep slopes imply complex binding phenomena, possibly involving multiple receptor types or affinity states. In such cases, the thermodynamic parameters should be separately determined for each receptor type or affinity state. 

NPY and its congeners act at multiple receptor types, belonging to the family of G-protein-coupled receptors. Several of the NPY-receptor types are promising targets for drug development and many pharmaceutical companies are carrying out research... 

The opioid peptides vary in their binding affinities for the multiple opioid receptor types. Leu- and Met-enkephalin have a higher affinity for 5-receptors than for the other opioid receptor types (68), whereas the dynorphin peptides have a higher affinity for K-sites (69). P-Endorphin binds with equal affinity to both p- and 5-receptors, but binds with lower affinity to K-sites (70). The existence of a P-endorphin-selective receptor, the S-receptor, has been postulated whether this site is actually a separate P-endorphin-selective receptor or is a subtype of a classical opioid receptor is a matter of controversy (71,72). The existence of opioid receptor subtypes in general is quite controversial although there is some evidence for subtypes of p- (73), 5-(74), and K-receptors (72,75), confirmation of which may be obtained by future molecular cloning studies. 

Psychiatric medicines exert multiple effects for two principal reasons. First, they usually interact with more than one receptor type. There are two ways to look at this. You will often hear a medication with multiple receptor interactions called a dirty drug. This is because the more receptor interactions it has, the more effects, and hence side effects, it produces. As a result, great effort has been made to develop newer medications with fewer receptor interactions and, thus, fewer side effects. This effort has been quite successful with antidepressants, as we have moved from the effective but side effect-laden tricyclic antidepressants to newer antidepressants such as selective serotonin reuptake inhibitors. 

But some feel that by reducing the receptor interactions we may produce less effective medications. In this view, medications with multiple receptor interactions are said to have a rich pharmacology. As we will see in a later chapter, these multiple actions in the synapse appear to be a reason why the newer atypical anti-psychotics have certain advantages over the older antipsychotic medicines. How many receptor interactions are sufficient How many are too many It depends. Certainly, it does no good to interact with a receptor that produces no benefit, but sometimes interacting with two different receptor types in a synergistic manner can produce even greater benefit. 

There is another reason why medications exert multiple effects. For example, an antidepressant that very specifically promotes serotonin neurotransmission and has little or no interaction with other receptor types will still produce multiple effects. How can this be Remember that in different areas of the brain, a single neurotransmitter can assume very distinct roles. When an individual takes a medication that alters the activity of a particular neurotransmitter, it generally does so throughout the brain. Consequently, the dopamine receptor blocking effect of haloperidol (Haldol) reduces hallucinations and paranoia in one brain region but causes upper extremity stiffness through its action in another brain region. 

What Is a Side Effect This chapter picks up where Chapters 1 and 2 left off. As we discussed in the earlier chapters, all medications, psychiatric and otherwise, have multiple effects. One takes a medication to achieve a therapeutic effect. Occasionally, a single medication may have more than one therapeutic effect. All other effects are side effects. Different medications may have differing therapeutic and side effects depending on the intended use. For example, trazodone and quetiapine are often prescribed to aid in sleep, and in this instance sedation is the desired effect, yet when used as an antidepressant and antipsychotic, respectively, the sedation is often an unwanted effect. Psychotropic medications typically have multiple effects. First, they usually interact with more than one nerve cell protein, be it a transporter or a receptor. Quite often, one of the medication s receptor or transporter interactions produces the therapeutic effect. The other interactions tend to not be involved in the therapeutic effect and only serve to produce side effects. Sometimes a neurotransmitter will have multiple different receptor types, but the medication interacts with... 

Fong TAT, Shawver LK, Sun L, et al. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-l/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res 1999 59 99-106. 

Serotonin (5-hydroxytryptamine 5-HT) acts as transmitter and mediator on several locations in the body with quite different effects. There are multiple sub-types of the serotonin receptor. This offers the possibility of a selective therapeutic interference using subtype specific agonists or antagonists. 

The dopamine beta-hydroxylase (Dbh) gene is necessary for the production of NE and epinephrine. Disruption of this gene results in the absence of NE and epinephrine production and is therefore used in studies determining the roles of these neurotransmitters. This approach is favored over the knockout of adrenergic receptors because of the multiplicity of receptor types for NE and epinephrine. 

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