Dihydrexidine, a novel selective high potency full dopamine D-1 receptor agonist

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998

910

The concept of intrinsic efficacy has been enshrined in pharmacology for half of a century, yet recent data have revealed that many ligands can differentially activate signaling pathways mediated via a single G protein-coupled receptor in a manner that challenges the traditional definition of intrinsic efficacy. Some terms for this phenomenon include functional selectivity, agonist-directed trafficking, and biased agonism. At the extreme, functionally selective ligands may be both agonists and antagonists at different functions mediated by the same receptor. Data illustrating this phenomenon are presented from serotonin, opioid, dopamine, vasopressin, and adrenergic receptor systems. A variety of mechanisms may influence this apparently ubiquitous phenomenon. It may be initiated by differences in ligand-induced intermediate conformational states, as shown for the ␤ 2 -adrenergic receptor. Subsequent mechanisms that may play a role include diversity of G proteins, scaffolding and signaling partners, and receptor oligomers. Clearly, expanded research is needed to elucidate the proximal (e.g., how functionally selective ligands cause conformational changes that initiate differential signaling), intermediate (mechanisms that translate conformation changes into differential signaling), and distal mechanisms (differential effects on target tissue or organism). Besides the heuristically interesting nature of functional selectivity, there is a clear impact on drug discovery, because this mechanism raises the possibility of selecting or designing novel ligands that differentially activate only a subset of functions of a single receptor, thereby optimizing therapeutic action. It also may be timely to revise classic concepts in quantitative pharmacology and relevant pharmacological conventions to incorporate these new concepts. Receptor Pharmacology for the New MillenniumFor the last half-century, pharmacological theory has posited that ligands could be characterized by the nature of the functional effects elicited by their interaction with their tar-

Section: Functional Selectivity At D 2l and D 1 Dopamine Receptorsmentioning

confidence: 99%

Functional Selectivity and Classical Concepts of Quantitative Pharmacology

Urban¹,

Clarke

Zastrow

et al. 2006

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998

910

“…The current work is a continuation of studies that may alter this tenet of pharmacology. Nearly a decade ago, we developed dihydrexidine, the first high-affinity, full dopamine D 1 receptor agonist (Lovenberg et al, 1989). Our preliminary characterization of this drug revealed, unexpectedly, that DHX had D 2 receptor affinity similar to the prototypical D 2 receptor agonist quinpirole (Brewster et al, 1990;Mottola et al, 1992).…”

mentioning

confidence: 93%

Functional Selectivity of Dopamine Receptor Agonists. II. Actions of Dihydrexidine in D_2LReceptor-Transfected MN9D Cells and Pituitary Lactotrophs

Kilts

Connery

Arrington³

et al. 2002

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D 2 -like dopamine receptors mediate functional changes via activation of inhibitory G proteins, including those that affect adenylate cyclase activity, and potassium and calcium channels. Although it is assumed that the binding of a drug to a single isoform of a D 2 -like receptor will cause similar changes in all receptor-mediated functions, it has been demonstrated in brain that the dopamine agonists dihydrexidine (DHX) and N-npropyl-DHX are "functionally selective". The current study explores the underlying mechanism using transfected MN9D cells and D 2 -producing anterior pituitary lactotrophs. Both dopamine and DHX inhibited adenylate cyclase activity in a concentrationdependent manner in both systems, effects blocked by D 2 , but not D 1 , antagonists. In the MN9D cells, quinpirole and R-(Ϫ)-N-propylnorapomorphine (NPA) also inhibited the K ϩ -stimulated release of [ 3 H]dopamine in a concentration-responsive, antagonist-reversible manner. Conversely, neither DHX, nor its analogs, inhibited K ϩ -stimulated [ 3 H]dopamine release, although they antagonized the effects of quinpirole. S-(ϩ)-NPA actually had the reverse functional selectivity profile from DHX (i.e., it was a full agonist at D 2L receptors coupled to inhibition of dopamine release, but a weak partial agonist at D 2L receptormediated inhibition of adenylate cyclase). In lactotrophs, DHX had little intrinsic activity at D 2 receptors coupled to G proteincoupled inwardly rectifying potassium channels, and actually antagonized the effects of dopamine at these D 2 receptors. Together, these findings provide compelling evidence for agonist-induced functional selectivity with the D 2L receptor. Although the underlying molecular mechanism is controversial (e.g., "conformational induction" versus "drug-active state selection"), such data are irreconcilable with the widely held view that drugs have "intrinsic efficacy".The dopamine receptors, members of the G protein-coupled receptor superfamily, are generally divided into two classes, "D 1 -like" and "D 2 -like" (Jaber et al., 1996;Huff, 1997) In the central nervous system, dopamine receptors exist on both dopamine neurons (on soma, dendrites, and terminals) and postsynaptically on target cells. Presynaptic receptors (autoreceptors) fall under the D 2 -like class of dopamine re-

“…Dihydrexidine (DHX) and related members of the hexahydrobenzo [a]phenanthridine class have been shown in previous publications to comprise a particularly interesting class of dopamine agonists (Lovenberg et al, 1989;Brewster et al, 1990Brewster et al, , 1995Mottola et al, 1992). In addition to its properties as a high-affinity, full D 1 receptor agonist, DHX also has affinity for D 2 receptors similar to the prototypical D 2 receptor agonist quinpirole.…”

mentioning

confidence: 99%

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

Mottola

Kilts

Lewis

et al. 2002

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114

107

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).