Functional Selectivity of Dopamine Receptor Agonists. I. Selective Activation of Postsynaptic Dopamine D₂Receptors Linked to Adenylate Cyclase

Abstract

Dihydrexidine (DHX), the first high-affinity D 1 dopamine receptor full agonist, is only 10-fold selective for D 1 versus D 2 receptors, having D 2 affinity similar to the prototypical agonist quinpirole. The D 2 functional properties of DHX and its more D 2 selective analog N-n-propyl-dihydrexidine (PrDHX) were explored in rat brain and pituitary. DHX and PrDHX had binding characteristics to D 2 receptors in rat striatum typical of D 2 agonists, binding to both high-and low-affinity sites and being sensitive to guanine-nucleotides. Consistent with these binding data, both DHX and PrDHX inhibited forskolin-stimulated cAMP synthesis in striatum with a potency and intrinsic activity equivalent to that of quinpirole. Unexpectedly, however, DHX and PrDHX had little functional effect at D 2 receptors expressed on dopaminergic neurons that mediate inhibition of cell firing, dopamine release, or dopamine synthesis. Quantitative receptor competition autoradiography demonstrated that DHX bound to D 2 receptors in striatum (predominantly postsynaptic receptor sites) with equal affinity as D 2 sites in the substantia nigra (autoreceptor sites). The data from these experiments, coupled with what is known about the location of specific dopamine receptor isoforms, lead to the hypothesis that DHX, after binding to D 2L and D 2S receptors, causes agonist-typical functional changes only at some of these receptors. This phenomenon (herein termed "functional selectivity") suggests that drugs may be targeted not only at specific receptor isoforms but also at separate functions mediated by a single isoform, yielding novel approaches to drug discovery. (D 2S ), D 3 , and D 4 . D 1 -like receptors preferentially recognize 1-phenyl-tetrahydrobenzazepines (e.g., SCH23390) over benzamides (e.g., sulpiride), whereas the D 2 -like receptors have the opposite pharmacological specificity. D 1 -and D 2 -like receptors have been defined traditionally by their opposing effects on the enzyme adenylate cyclase, with D 1 receptors positively coupled to this enzyme, whereas D 2 receptors are either negatively coupled or uncoupled to this effector. More recently, the actions of dopamine D 1 -and D 2 -like receptors on signaling systems other than adenylate cyclase have been confirmed in a variety of systems, including coupling to G protein inwardly rectifying potassium channels, phosphatidylinositol hydrolysis, and voltage-activated calcium channels (Jaber et al., 1996).

Aripiprazole, A Novel Atypical Antipsychotic Drug with a Unique and Robust Pharmacology

“…This mixture of agonist actions at D 2 -dopamine receptors is consistent with the hypothesis proposed by Lawler et al (1999) that aripiprazole has 'functionally selective' actions. The 'functional-selectivity' hypothesis proposes that, depending upon the cellular milieu (eg receptor and G protein complement and concentration), a mixture of agonist/partial agonist/antagonist actions are likely Lawler et al, 1999;Mottola et al, 2002). According to this hypothesis, agonists may induce structural changes in receptor conformations that are differentially 'sensed' by the local complement of G proteins to induce a variety of functional actions depending upon the precise cellular milieu.…”

“…There has been a long-standing hypothesis that D 2 partial agonists would be of particular utility in schizophrenia (Tamminga, 2002), and the developers of aripiprazole have proposed that the novel and improved clinical profile of aripiprazole is caused by the partial agonist properties at D 2 -dopamine receptors that result in 'dopamine stabilization' (Burris et al, 2002;Inoue et al, 1996). Conversely, it has been suggested (Lawler et al, 1999) that aripiprazole is not simply a partial agonist, but a drug whose D 2 functional effects were dependent on the cellular location (and signaling proteins) of the targeted D 2 receptor, a phenomenon termed 'functional selectivity' Lawler et al, 1999;Mottola et al, 2002) or 'agonist trafficking' (Kenakin, 1995). Whatever the mechanism, aripiprazole has been shown to be effective in treating the positive and negative symptoms of schizophrenia with a low incidence of side effects including minimal short-term weight gain, low liability for inducing movement disorders, and reductions (rather than elevations) in plasma prolactin levels (Goodnick and Jerry, 2002;Kane et al, 2002).…”

Human Neuropeptide S Receptor Is Activated via a Gαq Protein-biased Signaling Cascade by a Human Neuropeptide S Analog Lacking the C-terminal 10 Residues

“…This process has been termed biased signaling or functional selectivity (35)(36)(37). Biased activation of signaling path- ways by specific ligands has been documented for several other GPCRs, including dopamine D2R (38), the apelin receptor APJ (28), the ghrelin receptor GSHR1a (38), the type 1 parathyroid hormone receptor (39 -41), the urotensin II receptor (42), the V2 vasopressin receptor (43), the human free fatty acid receptor GPR120 (44), and the prokineticin receptor 2 (45). However, most GPCRs whose biased signaling has been investigated have exhibited bias between G protein-and arrestin-dependent pathways.…”

Kappa-Opioid Agonist U69593 Potentiates Locomotor Sensitization to the D2/D3 Agonist Quinpirole: Pre- and Postsynaptic Mechanisms

“…First, electrophysiological studies show that dopamine autoreceptors (Starke, 1981) are 3-10 times more sensitive to dopamine agonists, including QNP, than dopamine receptors located on postsynaptic cells in the striatum or the nucleus accumbens (Kelland et al, 1990;Skirboll et al, 1979;White and Wang, 1986). The typical autoreceptor effects, such as near total inhibition of spontaneous cell firing by midbrain dopamine neurons, can be produced with doses of QNP as low as 0.03 mg/kg (Mottola et al, 2002;Pitts et al, 1995). Moreover, strong support for the claim that this effect of QNP is produced by stimulation of dopamine autoreceptors is provided by findings that QNP is ineffective in D2 receptor null mice but continues to inhibit dopamine neuron activity in knockout mice lacking the D2Long isoform (Centonze et al, 2002), the isoform characteristic of the postsynaptic dopamine receptor (Khan et al, 1998;Usiello et al, 2000).…”