Di receptor

In view of the known cellular actions of DA, such as increased K+ efflux and reduced Ca + currents associated with Dj receptor activation in cell lines, inhibition would be the expected response to DA, especially as cyclic AMP, which is increased by Dj receptor activation also inhibits striatal neurons. In fact although many DA synaptic effects are blocked by Dj antagonists like haloperidol, the role of Di receptors should not be overlooked. 

It is perhaps not surprising that DA produces such mixed effects. The Di receptor is primarily linked to the activation of adenylate cyclase and then protein kinase A. The response to its activation will therefore depend on the ion channels and other proteins modulated by the kinase which can vary from one neuron to another. Since the D2 receptor is not so closely associated with just one G-protein, this gives it the potential for even more effects (see Greenhoff and Johnson 1997). 

On this evidence it appears that a Di agonist is only fully effective if endogenous DA is present to act on D2 receptors while a D2 agonist also requires, although not to the same extent, some DA to act on Di receptors. Of perhaps more importance is the fact that a full DA effect depends on the activation of both Di and D2 receptors even though the latter is dominant (Fig. 7.9). 

Calabresi, P, Mercuri, N, Stanzione, P, Stefani, A and Bernard, G (1987) Intracellular studies on the dopamine-induced firing inhibition of neostriatal neurons in vivo evidence for Di receptor involvement. Neurosciences 20 757-771. 

Since D2 (but not Di) receptors are expressed on neurons of the Ind Path, then D2 agonists will have the same effect on this pathway as levodopa and overcome the hypokinesia. Their inability to activate D] receptors could mean, however, that while they are less likely to cause dyskinesias, for the reasons given above, their ability to dampen the GPint may also not be sufficient to give the required facilitation of motor function. Conversely, the absence of Dj receptors on the Ind Path explains why their agonists carmot influence it and so appear unable to reduce hypokinesia. 

It is not surprising that a DA antagonist (especially those acting primarily on Di receptors) should produce the symptoms of Parkinsonism, a disorder caused by inadequate DA function (see Chapter 15), nor that its intensity or rate of onset over some weeks or months should increase with Dj antagonistic potency. Tolerance to this adverse effect can develop without affecting antipsychotic activity but the speed with which Parkinsonism resolves after stopping therapy may be from 3 to 12 months and can persist indefinitely in some cases. 

Its activity at Di receptors has been put forward as a possibility and although it has a relatively higher affinity for Di than Dj receptors, compared with typical neuroleptics, it is still a weak antagonist at both and in the absence of evidence for Di (or D5) receptor involvement in schizophrenia the significance of any Di antagonism is unclear. 

K (nM) values for clozapine at D2 and Di receptors are 56 and 141 compared with 0.5 and 27 for haloperidol giving D1/D2 ratios of 2.5 and 54 for the two drugs. A relatively strong block of Di compared with D2 receptors may not be the answer for schizophrenia but it could reduce the tendency to produce dyskinesias, if this depends on Di receptor activation (see Fig. 17.2). 

Negative symptoms. These may be reduced because either clozapine antagonises appropriate receptors in the prefrontal cortex or it does not act as an antagonist there. This apparently stupid statement is prompted by the lack of knowledge of what is required to reduce negative symptoms. D4 and Di receptors are found in the prefrontal cortex and only clozapine among current neuroleptics is more active at both of these than the D2 receptor. Thus on this basis it is well placed to block DA s... 

Altar, C.A., and Hauser, K. Topography of substantia nigra innervation by Di receptor-containing striatal neurons. Brain Res 410 1-11, 1987. Arushanian, E.B., and Belozertsev, Y.A. The effect of amphetamine and caffeine on the neuronal activity of the neocortex. Neuropharmacology 17 1-6, 1978. 

Other functional imaging studies of the DA system have reported decreased Di receptor density (Dagher et al. 2001), increased F-DOPA uptake (a marker for increased DA turnover) (Salokangas et al. 2000), and both decreased (Krause et al. 2002) and no alterations (Staley et al. 2001) in dopamine transporter binding in smokers. 

Detailed studies of the binding of H-labelled haloperidol to neuronal membranes showed that there was a much better correlation between the therapeutic potency of a neuroleptic and its ability to displace this ligand from the nerve membrane. This led to the discovery of two types of dopamine receptor that are both linked to adenylate cyclase but whereas the Di receptor is positively linked to the cyclase, the D2 receptor is negatively linked. It was also shown that the receptor is approximately 15 times more sensitive to the action of dopamine than the D2 receptor conversely, the receptor has a low affinity for the butyrophenone and atypical neuroleptics such as clozapine, whereas the D2 receptor appears to have a high affinity for most therapeutically active neuroleptics. 

The Di receptors have been subdivided into the Dia and Die types and are coded by genes located on chromosomes 5 and 4 respectively. Several selective antagonists of the receptors have been developed (for example, SCH 31966, SCH 23390 and SKF 83959), none of which have so far been developed for therapeutic use. 

Fig. 7.5 Schematic flowchart of the competitive MS-binding assay quantifying the nonbound marker employed for dopamine Di receptors. After incubation of the target (Di receptor) in presence of the marker (SCH 23390) and a test compound, the binding samples are centrifuged to separate bound from nonbound marker. The nonbound marker in the resulting supernatant is quantified by LC-ESI-MS/MS without further sample preparation.

Fig. 7.6 Nonbound SCH 23390 in a competitive MS binding assay for dopamine Di receptors monitored at a transition from 288.1 91.2 m/z from binding samples without or with (+)-butaclamol. Intensity (/) is shown (a) without (+)-butaclamol, (b) with 30 nM (+)-butaclamol, (c) with 10 pM (+)-butaclamol. (a-c) Representative chromatograms after HPLC separation (RP8 column solvent CH3CN/0.1% HCOOH in H2O 1 1 300 pL min ).

Fig. 7.7 Representative binding curve obtained by nonlinear regression from a competitive MS binding assay for dopamine Di receptors, in which (+)-butaclamol competes with SCH 23390 as marker. The points describe nonbound SCH 23390 quantified by LC-ESI-MS/MS. Data reflect means (+s) from binding samples, each performed in quadruplicate.

Di-receptors (comprising subtypes Di and D5) and D2-receptors (comprising subtypes D2, D3, and D4). The aforementioned actions are mediated mainly by D2 receptors. When given by infusion, dopamine causes dilation of renal and splanchnic arteries. This effect is mediated by Di receptors and is utilized in the treatment of cardiovascular shock and hypertensive emergencies by infusion of dopamine and fenoldopam, respectively. At higher doses, Pi-adrenoceptors and, finally, a-receptors are activated, as evidenced by cardiac stimulation and vasoconstriction, respectively. 

Dopamine is an intermediate product in the biosynthesis of noradrenaline. Furthermore it is an active transmitter by itself in basal ganglia (caudate nucleus), the nucleus accumbens, the olfactory tubercle, the central nucleus of the amygdala, the median eminence and some areas in the frontal cortex. It is functionally important, for example in the extra-pyramidal system and the central regulation of emesis. In the periphery specific dopamine receptors (Di-receptors) can be found in the upper gastrointestinal tract, in which a reduction of motility is mediated, and on vascular smooth muscle cells of splanchnic and renal arteries. Beside its effect on specific D-receptors, dopamine activates, at higher concentrations, a- and -adrenoceptors as well. Since its clinical profile is different from adrenaline and noradrenaline there are particular indications for dopamine, like situations of circulatory shock with a reduced kidney perfusion. Dopamine can dose-dependently induce nausea, vomiting, tachyarrhythmia and peripheral vasoconstriction. Dopamine can worsen cardiac ischaemia. 

A single in vivo cocaine administration abolishes endocannabinoid-depen-dent LTD. This effect of cocaine was not present in mice lacking Di dopamine receptors and was blocked by a selective Di receptor and NMDA receptor antagonist, suggesting the involvement of D i and NMDA receptors (Fourgeaud et al. 2004). 

A PET study using selective tracers for striatal dopamine Di ([ C]NNC 756) and striatal dopamine D2 ([ C]raclopride) receptors showed that while striatal D2 receptors were unaffected in patients with AD, striatal Di receptors were reduced by 14% in patients with AD compared with healthy age-matched controls [43]. At present, no F-labeled dopamine Di tracers have been validated for human PET studies. 

The Di receptor is typically associated with the stimulation of adenylyl cyclase (Table 9-1) for example, Di-receptor-induced smooth muscle relaxation is presumably due to cAMP accumulation in the smooth muscle of those vascular beds in which dopamine is a vasodilator. D2 receptors have been found to inhibit adenylyl cyclase activity, open potassium channels, and decrease calcium influx. 

Intravenous administration of dopamine promotes vasodilation of renal, splanchnic, coronary, cerebral, and perhaps other resistance vessels, via activation of Di receptors. Activation of the Di receptors in the renal vasculature may also induce natriuresis. The renal effects of dopamine have been used clinically to improve perfusion to the kidney in situations of oliguria (abnormally low urinary output). The activation of presynaptic D2 receptors suppresses norepinephrine release, but it is unclear if this contributes to cardiovascular effects of dopamine. In addition, dopamine activates Bj receptors in the heart. At low doses, peripheral resistance may decrease. At higher rates of infusion, dopamine activates vascular a. receptors, leading to vasoconstriction, including in the renal vascular bed. Consequently, high rates of infusion of dopamine may mimic the actions of epinephrine. 

Fenoldopam is a Di-receptor agonist that selectively leads to peripheral vasodilation in some vascular beds. The primary indication for fenoldopam is in the intravenous treatment of severe hypertension (Chapter 11). 

Bromocriptine (as the mesylate) has agonistic activity at brain Di receptors and antagonistic activity at D2 receptors. 

H]TCIB, has been obtained145 starting with 5-chloroisatoic anhydride 160 and catalytic tritiolysis of 161 (equation 75). 159 is considered a valuable tool to study the structure, function and pharmacological role of DI receptors ( diazepine insensitive subtype of benzoadepine receptor146, BZR). 

Iodinated radiographic contrast media can cause acute renal insufficiency, perhaps as a result of reduced renal blood flow, an intrarenal osmotic effect, or direct tubular toxicity (58). Diuretics, calcium channel blockers, adenosine receptor antagonists, acetylcysteine, low-dose dopamine, the dopamine Di receptor agonist fenoldopam, endothelin receptor antagonists, and captopril have all been used to prevent contrast nephropathy. 

---