D2-agonists

Deca/octahydro 6-alkyloxazolo /-fused quinolines 17 were prepared and evaluated as dopaminergics (87EUP1). A series of linearly annelated 8-alkyl-deca/ octahydrooxazoloquinolines 18 and their salts were prepared for use as dopamine D2-agonists and hypertensive agents. The rran.s-( )-l-propyl-6-oxodecahydro-quinoline was brominated, then treated with urea in methanol to give the 2-amino... 

Hillefors-Berglund M, Liu Y, von Euler G Persistent, specific and dose-dependent effects of toluene exposure on dopamine D2 agonist binding in the rat caudate-putamen. Toxicology 77 223-232, 1993... 

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). 

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. 

Cory-Slechta DA, Widzowski DV. 1991. Low level lead exposure increases sensitivity to the stimulus properties of dopamine D1 and D2 agonists. Brain Res 553 65-74. 

Ranaldi R., Beninger R. The effects of systemic and intracerebral injections of D, and D2 agonists on brain stimulation reward. Brain Res. 651 283, 1994. 

Which of the following agents is a selective dopamine receptor (D2) agonist ... 

The answer is b. (Hardman, pp 282—283J Central dopamine receptors are divided into Dt and D2 receptors. Antipsychotic activity is better correlated to blockade of D2 receptors. Haloperidol, a potent antipsychotic, selectively antagonizes at Dz receptors. Phenothiazine derivatives, such as chlorpromazine, fluphenazine, and promethazine, are not selective for D2 receptors. Bromocriptine, a selective D2 agonist, is useful in the treatment of parkinsonism and hyperprolactinemia. It produces fewer adverse reactions than do nonselective dopamine receptor agonists... 

Dopamine-sensitive adenylate cyclase activity was early demonstrated in both the retina and the cervical ganglion of the cow [47] and later in homogenates of the caudate-putamen of the rat brain [48]. Kebabian has recently reviewed the biochemical components of dopamine-sensitive adenylate cyclase and the physiological role of the D1 receptor [49]. D1 and D2 agonists stimulate and inhibit adenylate cyclase activity, respectively. 

Locomotor activity is measured in motility boxes equipped with photocells. Both horizontal and vertical movements can be registered in the modern boxes. Pretreatment with reserpine (18 h) renders the animals virtually without movement, an akinetic Parkinson-like state. It also makes postsynaptic D2 receptors supersensitive, since the receptors have been exposed to low concentrations of DA for a long period of time. The model is thus useful to reveal D2 agonists with a low degree of intrinsic efficacy and, the intrinsic efficacy of a series of partial agonists can be rated by this model. 

The dopamine D2 agonist SAR area has been reviewed by Hacksell and coworkers from the perspective of stereochemistry and pharmacological profiles of the enantiomers of the compounds synthesized by that research group during a period of 10 years. The structural classes surveyed were 3-phenylpiperidines, 2-aminotetralins and their ring-methylated analogues and octahydrobenzo[/]quinolines (OHB[f]Qs) [60]. 

A new and detailed tetralin study deals with the resolution and the determination of the optical purity of the enantiomers of 5-OH-DPAT (21). Of particular interest is that an analytical HPLC method that measures very small amounts of optical impurity was used [72]. It could be shown that the i -enantiomer really possesses antagonistic properties, as measured biochemically, in non-pretreated animals [73]. These findings support the modelling results of Froimowitz and co-workers [74,75]. Other studies have not revealed such properties of (/ -21) [64,76]. These new and interesting findings have implications for the atypical D2 antagonsits with preferential action on D2 autoreceptors, developed from D2 agonists, as discussed below. 

I 72 CPCR-specific Combinational Libraries Based on the Concept of Privileged Substructures Tab. 12.4 Some privileged structural motifs of Dopamine D2 agonists... 

Fig. 12.5 Dopamine D2 agonists having a distinct N-arylpiperazine privileged motif and structurally different peripheral fragments.

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