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A series of [4-[2(4-arylpiperazin-1-yl)alkyl]cyclohexyl]pyrimidin-2-ylamine s was prepared and found to have receptor binding affinity for D2 and D3 dopamine (DA) receptors and serotonin 5-HT1A receptors. The structural contributions to D2/D3 and 5-HT1A receptor binding of the aminopyrimidine, cycloalkyl, and phenylpiperazine portions of the molecule were examined. From these studies compounds 14, 39, 42, 43, having potent affinity for both DA D2 and 5-HT1A receptors, were evaluated for intrinsic activity at these receptors, in vitro and in vivo. Compound 14 (PD 158771) had a profile indicative of partial agonist activity at both D2 and 5-HT1A receptors causing partially decreased synthesis of the neurotransmitters DA and 5-HT and their metabolites. This compound has a profile in behavioral tests that is predictive of antipsychotic activity, suggesting that mixed partial agonists such as 14 may have utility as antipsychotic agents with increased efficacy and decreased side effects.

In the search for drugs against schizophrenia and depression without extrapyramidal side effects, compounds that selectively antagonize the dopamine D3 receptor subtype are thought to be a solution. In order to create a model with which the D3 activity can be predicted and that can generate new ideas for future synthesis, we performed a comparative molecular field analysis (CoMFA). In our model 30 ligands were described quantitatively in the GRID program, and the model was optimized by selecting only the most informative variables in the GOLPE program. We found the predictive ability of the model to increase significantly when the number of variables was reduced from 25 110 to 784. A Q 2 of 0.65 was obtained with the final model, confirming the predictive ability of the model. By studying the PLS coefficients in informative 3D contour plots, ideas for the synthesis of new compounds can be generated.

A series of 4-bromo-1-methoxy-N-[2-(4-aryl-1-piperazinyl)ethyl]-2-naphthalenecarboxamide dopamine (DA) D 3 receptor agonists has been identified. These compounds were found to be selective for DA D 3 over D 2 receptors and were shown to be partial to full agonists as measured by stimulation of mitogenesis in D 3 -transfected CHO p-5 cells.

The pyridine analogs of 5-hydroxy-2-(di-n-propylamino)tetralin (5-OH-DPAT), 4-6, were synthesized, and their biological activity was compared to that of 5-OH-DPAT. Compounds 4 and 6 exhibited activity similar to 5-OH-DPAT in dopamine (DA) D2 and D3 receptor binding and in autoreceptor activation as measured by their ability to reverse the gamma-butyrolactone-induced increase in rat DA synthesis. Behaviorally, 4 and 6 decreased locomotor activity (LMA) in rats (sc) at low doses but did not increase LMA to the same extent as 5-OH-DPAT at higher doses, indicating that 4 and 6 may be more selective for the DA autoreceptor. While 4 was less active orally in rats, 6 appeared to retain most of its behavioral potency. Analog 5 showed little activity in vivo or in vitro.

As part of a discovery effort aimed at identifying novel norepinephrine reuptake inhibitors (NRIs), a number of substituted morpholines were designed and synthesized. The target compounds contain vicinal stereogenic centers, and the program was greatly facilitated by the adoption of efficient synthetic routes which allowed for the late stage incorporation of structural and physicochemical diversity into the targets. Structure-activity relationships were developed by optimizing individual ring components of the structure for NRI potency and for selectivity against other monoamine reuptake transporters. Several novel morpholine derivatives with a potent and selective NRI profile are described.

Publisher Summary This chapter presents new therapeutic approaches for the treatment attention-deficit/hyperactivity disorder (ADHD) such as monoamine reuptake inhibitors, Dopamine D 4 antagonists, α 2 -Adrenergic agonists, histamine H 3 antagonists, and nicotinic receptor agonists. There is considerable documentation supporting the association between the 7-repeat allele of the dopamine D 4 receptor and the personality trait of novelty seeking and ADHD, especially the inattention subtype. It has been shown that motor hyperactivity in 6-hydroxydopamine lesioned juvenile rats can be dose-dependently inhibited by stimulants used to treat ADHD and selective antagonists for the dopamine D 4 but not D2 receptors. The α 2 -adrenergic agonists clonidine and guanfacine have been used in the treatment of ADHD especially where co-morbid tic disorders can be exacerbated by stimulants. The synthesis and release of histamine, H 3 receptors are heteroreceptors that modulate the release of a number of other neurotransmitters that are implicated in the learning and motor disturbances in ADHD; these include DA, NE and acetylcholine. H3 antagonists have been shown to enhance attention and cognition in multiple animal models.

A novel series of aryl 1-but-3-ynyl-4-phenyl-1,2,3,6-tetrahydropyridines with dopaminergic activity is described. The structure-activity relationships of this series were studied by synthesis of analogs and evaluation of their affinities for the dopamine (DA) D2 receptor and inhibition of locomotor activity (LMA) in rodents. The basic amine, alkyne chain length, and aryl groups were varied. Compounds having a 4-phenyl-1,2,3,6-tetrahydropyridine and an aryl group with hydrogen-bonding substituents separated by a butynyl chain were found to have the most potent dopaminergic activity. Several compounds that were found to have exceptional in vivo activity in LMA inhibition in rodents were evaluated for additional pharmacological activity including binding affinities for other DA receptor subtypes as well as effects on brain DA synthesis, DA neuronal firing, and conditioned avoidance responding in squirrel monkeys.