D-2 receptor agonists

Monti J., Hawkins M., Jantos H., DAngelo L., Fernandez M. (1988). Biphasic effects of dopamine D-2 receptor agonists on sleep and wakefulness in the rat. 

Thus, amphetamine-like drugs may promote wakefulness primarily by increasing dopaminergic tone. Accordingly, it has been found that intracerebroventric-ular infusion of D-l and D-2 receptor agonists in sleeping rats induces a dose-dependent increase in time awake (Benerjee et al. 2004). 

Figure 3. D-2 receptor agonists, RU 24926 and LY 141865, inhibit the K -stimulated release of [3H]-acetylcholine from blocks of rat neostriatum. (Reproduced with permission from Ref. 96. Copyright, Elsevier Biomedical Press.)...

The possibility that dopamine regulates neostriatal GABA-ergic function receives no support from in vitro superfusion experiments determining the release of [3HJ-GABA from slices of rat neostriatum (5 3). The D-2 receptor agonist RU 24926 is... 

Figure 9. D-2 receptor agonist LY 141865 inhibits the K -stimulated release of...

Zhao, D. and Ren, L.M. (2003) Electrophysiological responses to imidazoline/alpha(2)-receptor agonists in rabbit sinoatrial node pacemaker cells. ActaPharmacolo caSinica,U, 1217-1223. 

Other drug effects that decrease DA activity also support this position. Thus, when DA synthesis is blocked by a-methyl- p-tyrosine (AMPT), the dose necessary for an antipsychotic effect is reduced (i.e., the dose-response curve is shifted to the left by the interaction between dopamine and AMPT). A drug such as reserpine that can deplete DA stores also has relatively mild antipsychotic properties. Also, aripiprazole, which has D 2 presynaptic agonist properties, decreases the production of DA, as well as blocking D2 postsynaptic receptors. 

Activation of neostriatal tyrosine hydroxylase was observed when cyclic AMP was added to high speed supernatants from rat neostriatum (133). Intraventricular injection of dibutyryl cyclic AMP stimulated tyrosine hydroxylation in the neostriatum (134). However, it is still questionable if under physiological conditions this cyclic AMP involvement in the feedback control of tyrosine hydroxylase activity is mediated by presynaptic dopamine receptors or by presynaptic allo-receptors. In addition, if a dopamine sensitive adenylate cyclase is involved in the regulation of neostriatal tyrosine hydroxylase activity it is relevant to know if this adenylate cyclase is linked to a D-1 and/or a D-2 receptor. At this point in time experimental data are not in favour of the presence of a D-l receptor linked to an adeiylate cyclase on the varicosities of dopaminergic neurons in the neostriatum. E.g. concentrations of dopamine agonists stimulating cyclic AMP formation inhibit tyrosine... 

All the DA agonists employed clinically activate D-2 receptors, but none are entirely selective. Some also stimulate... 

Daly SA, Waddington JL (1993) Behavioural effects of the putative D-3 dopamine receptor agonist 7-OH-DPAT in relation to other D-2-like agonists. Neuropharmacology 32 509-510. 

Vilner, B.J., Bowen, W.D., 1997. Sigma-2 receptor agonists induce apoptosis in rat cerebellar granule cells and human SK-N-SH neuroblastoma cells. Society for Neuroscience Abstracts 23 (905.6), 2319. 

The present view is that D-2, as a high-affinity species, represents the presynaptic autoreceptor in the CNS. The low-affinity D-2 receptor, then, is postsynaptic. D2 receptors are not coupled to c-AMP as a secondary messenger. Their mass is estimated as 136,700 daltons. The structural variety of D-2 antagonists varies considerably and includes many clinically important groups of antipsychotic drugs the phenothiazine tranquilizers and several of their bioisosteres (the butyrophenones), a dibenzodiazepine (clozapine), the indole derivative molindone, and a benzamide (sulpiride), all to be discussed later. The ergot alkaloids represent D-2 agonists. 

Dopamine Receptors - All antipsychotic drugs (neuroleptics) are known to block DA receptors. The number of receptor subtypes claimed for DA, based on binding studies, include "D-1, D-2, D-3 and D-4". 5 However, only the postsynaptic D-2 receptors (labeled by 3[H]butyrophenones) are most consistently relatable to the effects of drugs. The D-1 subtype, a DA-stimulated adenylate cyclase site, has no clearcut function in brain. 46 Recent studies on agonist binding disclosed that 3[h]DA binds to two sites, both postsynaptic one is related to D-2 sites and the other to D-1 sites. 47... 

Data for the D-2 receptor were obtained in experiments determining the release of IR-aMSH from enzymatically dispersed intermediate lobe cells. For the D-2 agonists, the value in parenthesis is the maximal agonist-induced inhibition of L-isoproterenol-stimulated release of IR-qiMSH expressed as a percentage of the inhibition due tol mM LY 171555 affinity is the concentration of the indicated agent causing half-maximal inhibition of L-isoproterenol-stimulated release of IR-aMSH. For S(+)APO, affinity is the inhibition constant (Ki). 

FIGURE 5.19 Method of Barlow for measurement of affinity of a partial agonist, (a) Guinea pig ileal smooth muscle contraction to histamine (filled circles) and partial histamine receptor agonist E-2-P (N,N-diethyl-2-(l-pyridyl)ethylamine (open circles). Dotted lines show equiactive concentrations of each agonist used for the double reciprocal plot shown in panel b. (b) Double reciprocal plot of equiactive concentrations of histamine (ordinates) and E-2-P (abscissae). Linear plot has a slope of 55.47 and an intercept of 1.79 x 10s. This yields a KB (1 — tp/ta) = 30.9 pM. (c) Variant of double reciprocal plot according to Equation 5.8. (d) Variant of double reciprocal plot according to Equation 5.10. Data redrawn from [10],... 

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