Structure-activity relationships of pregabalin and analogues that target the alpha(2)-delta protein.

Pregabalin exhibits robust activity in preclinical assays indicative of potential antiepileptic, anxiolytic, and antihyperalgesic clinical efficacy. It binds with high affinity to the alpha(2)-delta subunit of voltage-gated calcium channels and is a substrate of the system L neutral amino acid transporter. A series of pregabalin analogues were prepared and evaluated for their alpha(2)-delta binding affinity as demonstrated by their ability to inhibit binding of [(3)H]gabapentin to pig brain membranes and for their potency to inhibit the uptake of [(3)H]leucine into CHO cells, a measure of their ability to compete with the endogenous substrate at the system L transporter. Compounds were also assessed in vivo for their ability to promote anxiolytic, analgesic, and anticonvulsant actions. These studies suggest that distinct structure activity relationships exist for alpha(2)-delta binding and system L transport inhibition. However, both interactions appear to play an important role in the in vivo profile of these compounds.

Orally active analogues of the dopaminergic prodrug 6-(N,N-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one: synthesis and pharmacological activity.

A series of analogues of 6-(N,N-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one (6), an enone prodrug of the mixed DA D(1)/D(2) agonist 5,6-diOH-DPAT (2), was synthesized. The pharmacological profiles of these new enones and their in vivo pharmacological activities were investigated in the Ungerstedt rat rotation model for Parkinson's disease. At 0.1 mg kg(-1) po, the N-methyl-N-n-propyl (12) and the N-ethyl-N-propyl (13) analogues induced pronounced and long lasting pharmacological effects. The pharmacological profile of enone 12 was found to be similar to that of 6, while enone 13 was significantly more potent than 6 (p < 0.01). Analyses of rat brains after the administration of (-)-6 and 13 indicated the presence of hydroxylated metabolites of the parent enones. It is speculated that such metabolites are alpha'-hydroxylated enones that may constitute the first step in the formation of the corresponding catechols.

The discovery of PD 89211 and related compounds: selective dopamine D4 receptor antagonists.

The dopamine (DA) D2 family of receptors consists of the D2, D3, and D4 receptors. The DA D4 receptor is of interest as a target for drugs to treat schizophrenia based upon its high affinity for the atypical antipsychotic clozapine and its localization to the limbic and cortical regions of the brain. As part of a program to identify novel DA D4 receptor antagonists, a high-volume screen using the Parke-Davis compound library was initiated. This led to the discovery of PD 89211 (benzenemethanol, 2-chloro-4-[4-[(1H-benzimidazol-2-yl)methyl]-1-piperzinyl]) that displaced [3H]spiperone binding to hD4.2 with an affinity (Ki) of 3.7 nM. PD 89211 exhibited high selectivity for the DA D4.2 receptor (> 800-fold) as compared to other hDA receptor subtypes, rat brain serotonin, and adrenergic receptors. In vitro, PD 89211 had D4 receptor antagonist activity reversing quinpirole-induced [3H]thymidine uptake in CHOpro5 cells (IC50 = 2.1 nM). Limited structure-activity relationship (SAR) studies indicated that compounds with a 4-chloro-, 4-methyl-, and 3-chloro- substituents on the phenyl ring retained high affinity for D4 receptors, while those with a 4-methoxy- and no substituent had less affinity. While all clinically effective antipsychotics increase DA synthesis (DOPA accumulation) in rodents, PD 89211 did not increase DA synthesis in the DA-enriched striatum, indicating no effect on DA turnover and low propensity for exhibiting motor side effects. However, it did increase catecholamine synthesis in rat hippocampus, as did clozapine. Moreover, PD 89211 selectivity increased catecholamine synthesis in the hippocampus of wild type but not in mice lacking D4 receptors, suggesting that one function of D4 receptors may be to modulate DA/norepinephrine (NE) turnover in this brain area known to possess D4 receptors. The discovery of compounds like PD 89211 provides a tool to help in understanding the function of DA D4 receptors in the CNS.