Some implications of receptor theory for in vivo assessment of agonists, antagonists and inverse agonists

Abstract

Drug effects can be classified into three major phenotypes: agonist, antagonist and inverse agonist. Agonist and inverse agonist effects are associated with receptor activation and inactivation, respectively, whereas antagonism implies that a drug produces no effect when administered alone but blocks the effects of agonists and inverse agonists. Attention has only recently begun to focus on the theoretical and clinical implications of inverse agonists, and studies of inverse agonism have also stimulated revisions in receptor theory. This commentary addresses two specific issues related to the application of receptor theory to studies of inverse agonists in vivo. First, principles of receptor theory suggest that increasing drug doses produce a graded pharmacological stimulus that is transduced by receptor-containing tissue into a biological response. However, assays vary in their ability to detect those responses, and any given assay provides only a narrow window on the full range of underlying drug effects. Consequently, in vivo assessment of inverse agonists will benefit from development of assays sensitive to graded inverse agonist effects. Second, detection of inverse agonist effects requires some preexisting level of receptor activity (or tone). This tone can result from at least two sources: (a) endogenous ligands for the receptor, or (b) constitutive receptor activity. Strategies for discriminating these two sources of tone will also contribute to the in vivo assessment of inverse agonist effects. Studies with intermediate efficacy ligands may be especially helpful in this regard, because their effects are differentially influenced by endogenous agonist tone versus constitutive receptor tone. KeywordsInverse agonist; Agonist; Antagonist; Receptor theory; In vivo; Constitutive activityThe terms "agonist", "antagonist", and most recently, "inverse agonist" have evolved to describe different profiles of drug effects. By convention, an agonist is considered to be a drug that activates receptors to produce a measurable effect in some assay. A full agonist produces a maximal effect under a given set of conditions, whereas a partial agonist produces a detectable but submaximal effect. Conversely, an inverse agonist produces an effect opposite to that of an agonist, and inverse agonists can also be "full" or "partial". An antagonist produces no effect on its own but blocks the effects of both agonists and inverse agonists. In the first study to demonstrate inverse agonist activity at a G-protein-coupled receptor (the delta opioid receptor), the delta opioid [D-Ala-2 -D-Leu-5 ]enkephalin increased GTPase activity in membranes from a cell line that expresses delta receptors (i.e. an agonist effect), whereas ICI174864 reduced GTPase activity below basal levels (i.e. an inverse agonist effect), and the effects of both drugs were blocked by MR2266 (an antagonist effect) [1].

Discriminative Stimulus Effects of 1-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane (DOM), Ketanserin, and (R)-(+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-pipidinemethanol (MDL100907) in Rats

“…Little is known about constitutive activity and inverse agonism in vivo, in part, because of difficulties (e.g., endogenous ligand binding) that are inherent to studies in vivo (e.g., Negus, 2006). Notwithstanding a paucity of in vivo data, there is evidence for constitutive activity of 5-HT 2A receptors and for inverse agonist actions of drugs acting at these receptors (for reviews, see Harvey, 2003;Aloyo et al, 2009).…”

Uncovering the Pharmacology of the G Protein-Coupled Receptor GPR40: High Apparent Constitutive Activity in Guanosine 5′-O-(3-[35S]thio)triphosphate Binding Studies Reflects Binding of an Endogenous Agonist

“…This type of dilemma can be resolved if both inverse agonists and neutral antagonists are available for a GPCR. However, for recently characterized GPCRs with limited small-molecule pharmacology, this poses considerable challenges and has been the most limiting issue in defining the contribution of constitutive activity to the physiological function of GPCRs (Gardner and Mallet, 2006;Negus, 2006). It is thus sensible to simply refer to GW1100 as a GPR40 antagonist until this issue can be clearly defined.…”

Effects of Two Novel D3-Selective Compounds, NGB 2904 [N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)butyl)-9H-fluorene-2-carboxamide] and CJB 090 [N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin-2-yl)benzamide], on the Reinforcing and Discriminative Stimulus Effects of Cocaine in Rhesus Monkeys

“…Partial agonists may provide a unique versatility as a potential pharmacotherapeutic treatment because the efficacy of the compounds should vary with levels of extracellular DA competing for the receptor (Pulvirenti and Koob, 1994;Childress and O'Brien, 2000;Platt et al, 2002;Negus, 2006). In contrast, an antagonist would be expected to decrease cocaine seeking and decrease the positive subjective effects of cocaine, irrespective of levels of extracellular DA jpet.aspetjournals.org (Platt et al, 2002).…”