Cloning, expression, functional coupling and pharmacological characterization of the rat dopamine D 4 receptor

Section: Discussionsupporting

confidence: 84%

Y₄ Receptors Mediate the Inhibitory Responses of Pancreatic Polypeptide in Human and Mouse Colon Mucosa

Tough¹,

Holliday²,

Cox³

2006

“…at ASPET Journals on May 7, 2018 jpet.aspetjournals.org sion of G␣ o , consistent with previous reports documenting poor coupling (Gazi et al, 2000). Constitutive internalization of the receptor has been proposed to explain the poor coupling observed with D 4 (Oldenhof et al, 1998 (Jardemark et al, 2002); however, the data presented above suggest that D 4 does not mediate the therapeutic effects of antipsychotic medications nor does selectivity for D 4 predict atypicality, in agreement with previous results (Roth et al, 1995).…”

Section: Intrinsic Efficacy Of Antipsychotics 1283supporting

confidence: 91%

“…However, a comprehensive efficacy profile of compounds that target D 2 -like receptors is lacking. The impact of inverse agonism upon the clinical properties of these compounds is not fully understood, in part because the low sensitivity of many functional assays prevents reliable measurements of constitutive activity, and precludes functional assessment of receptors that signal poorly in heterologous systems such as D 3 (see Newman-Tancredi et al, 1999) and D 4 receptors (see Oldenhof et al, 1998;Gazi et al, 2000). Previously, we have shown that overexpression of G-proteins increases assay sensitivity and induces constitutive activity of GPCRs (Burstein et al, 1997).…”

mentioning

confidence: 99%

Intrinsic Efficacy of Antipsychotics at Human D₂, D₃, and D₄Dopamine Receptors: Identification of the Clozapine MetaboliteN-Desmethylclozapine as a D₂/D₃Partial Agonist

Burstein¹,

Ma²,

Wong³

et al. 2005

165

103

Drugs that antagonize D 2 -like receptors are effective antipsychotics, but the debilitating movement disorder side effects associated with these drugs cannot be dissociated from dopamine receptor blockade. The "atypical" antipsychotics have a lower propensity to cause extrapyramidal symptoms (EPS), but the molecular basis for this is not fully understood nor is the impact of inverse agonism upon their clinical properties. Using a cell-based functional assay, we demonstrate that overexpression of G␣ o induces constitutive activity in the human D 2 -like receptors (D 2 , D 3 , and D 4 ). A large collection of typical and atypical antipsychotics was profiled for activity at these receptors. Virtually all were D 2 and D 3 inverse agonists, whereas none was D 4 inverse agonist, although many were potent D 4 antagonists. The inverse agonist activity of haloperidol at D 2 and D 3 receptors could be reversed by mesoridazine demonstrating that there were significant differences in the degrees of inverse agonism among the compounds tested. Aripiprazole and the principle active metabolite of clozapine NDMCwere identified as partial agonists at D 2 and D 3 receptors, although clozapine itself was an inverse agonist at these receptors. NDMC-induced functional responses could be reversed by clozapine. It is proposed that the low incidence of EPS associated with clozapine and aripiprazole used may be due, in part, to these partial agonist properties of NDMC and aripiprazole and that bypassing clozapine blockade through direct administration of NDMC to patients may provide superior antipsychotic efficacy.

“…hD 4 Receptors. In line with studies of CHO cells expressing the hD 4.2 isoform (Gilliland and Alper, 2000) and of cloned, rat D 4 sites (Gazi et al, 2000), quinpirole showed substantial efficacy at hD 4 (hD 4.4 ) receptors. This characteristic was shared by quinerolane and TL99.…”

Section: Discussionsupporting

confidence: 53%

“…This characteristic was shared by quinerolane and TL99. The agonist properties of pergolide, apomorphine, talipexole, and pramipexole at hD 4 sites complement work using other measures of drug efficacy and/or other hD 4 isoforms (Mieurau et al, 1995;Coldwell et al, 1999;Gazi et al, 2000;Gilliland and Alper, 2000). Like pergolide, two other ergolines, cabergoline and lisuride, similarly showed agonist properties at hD 4 sites.…”

Section: Discussionmentioning

confidence: 77%

Differential Actions of Antiparkinson Agents at Multiple Classes of Monoaminergic Receptor. II. Agonist and Antagonist Properties at Subtypes of Dopamine D₂-Like Receptor and α₁/α₂-Adrenoceptor

Newman‐Tancredi¹,

Cussac²,

Audinot³

et al. 2002

171

133

The accompanying multivariate analysis of the binding profiles of antiparkinson agents revealed contrasting patterns of affinities at diverse classes of monoaminergic receptor. Herein, we characterized efficacies at human (h)D 2SHORT(S) , hD 2LONG(L) , hD 3 , and hD 4.4 receptors and at h␣ 2A -, h␣ 2B -, h␣ 2C -, and h␣ 1A -adrenoceptors (ARs). As determined by guanosine 5Ј-O-(3-[ S]GTP␥S) binding, no ligand displayed "full" efficacy relative to dopamine (100%) at all "D 2 -like" sites. However, at hD 2S receptors quinpirole, pramipexole, ropinirole, quinerolane, pergolide, and cabergoline were as efficacious as dopamine (E maxՆ 100%); TL99, talipexole, and apomorphine were highly efficacious (79 -92%); piribedil, lisuride, bromocriptine, and terguride showed intermediate efficacy (40 -55%); and roxindole displayed low efficacy (11%). For all drugs, efficacies were lower at hD 2L receptors, with terguride and roxindole acting as antagonists. At hD 3 receptors, efficacies ranged from 33% (roxindole) to 94% (TL99), whereas, for hD 4 receptors, highest efficacies (ϳ70%) were seen for quinerolane, quinpirole, and TL99, whereas piribedil and terguride behaved as antagonists and bromocriptine was inactive. Although efficacies at hD 2S versus hD 2L sites were highly correlated (r ϭ 0.79), they correlated only modestly to hD 3 /hD 4 sites (r ϭ 0.44 -0.59). In [ 35 S]GTP␥S studies of h␣ 2A -ARs, TL99 (108%), pramipexole (52%), talipexole (51%), pergolide (31%), apomorphine (16%), and quinerolane (11%) were agonists and ropinirole and roxindole were inactive, whereas piribedil and other agents were antagonists. Similar findings were obtained at h␣ 2B -and h␣ 2C -ARs. Using (Wang et al., 2000). As shown in the accompanying article , therapeutically used antiparkinson agents recognize D 2S and D 2L isoforms with similar affinity, and many antiparkinson agents also interact with dopamine D 3 receptors. Although the density of striatal D 3 receptors is reduced upon degeneration of nigrostriatal dopaminergic pathways, exposure to L-DOPA may induce their up-regulation, reflecting complex regulatory mechanisms involving dopamine D 1 receptors and brainderived neurotrophic factor (Quik et al., 2000;Guillin et al., 2001;Joyce, 2001). Nevertheless, the precise nature of functional interrelationships among D 3 , D 2 , and D 1 receptors, and the implication of D 3 receptors in the therapeutic comArticle, publication date, and citation information can be found at