Thomas G. Heffner

Pyrazolo[1,5-a]pyrimidine CRF-1 receptor antagonists

A series of 3-phenylpyrazolo[1,5-a]pyrimidines was prepared and found to have affinity for the human CRF-1 receptor. The 3-dimensional structure of one of the most potent analogs in this series, 10d, was determined by X-ray crystallography and suggests the spatial requirements for potent CRF-1 receptor binding affinity in this series.

Reduced amide bond neurotensin 8-13 mimetics with potent in vivo activity

Abstract Appropriately substituted 8–9 (ΨCH2NH) isosteres of neurotensin (NT) 8–13 have been found which are active as NT agonists in vitro and in vivo. SAR studies suggest that preventing amide bond hydrolysis at the 8–9 and 11–12 positions of NT(8–13) mimetics is important for producing compounds with potent activity in vivo. Other simplified replacements for the Arg-Arg portion of NT(8–13) are reported.

Ribose-modified adenosine analogues as adenosine receptor agonists

Analogues of the potent adenosine receptor agonist (R)-N-(1-methyl-2-phenylethyl)adenosine (R-PIA), modified at N9, were prepared and evaluated for adenosine A1 and A2 receptor binding and in vivo central nervous system and cardiovascular effects. The modifications at N9 include deoxy sugars, 5-substituted-5-deoxyriboses, non-ribose sugars, sugar ring homologues, and acyclic sugar analogues. Most of the derivatives have poor affinity for adenosine receptors. Only minor modifications at C5 and C3 maintain potent binding. In general, those derivatives exhibiting in vivo behavioral or cardiovascular effects also have the highest affinity for adenosine receptors.

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.

PD 158771, a potential antipsychotic agent with D2/D3 partial agonist and 5-HT1A agonist actions. I. Neurochemical effects

The neurochemical effects of a novel dopamine (DA) D(2)-like and serotonin (5-HT) 5-HT(1A) agonist, PD 158771, are described. PD 158771 exhibited affinities for human D(2L), D(3) and D(4.2) receptors expressed in Chinese hamster ovary (CHO)-K1 cells with K(i) (nM) values of 5.2, 13.7 and 34.8 respectively. PD 158771 showed high affinity for cloned human 5-HT(1A) (K(i) = 2.6 nM) and rat hippocampal 5-HT(1A) receptors (K(i) = 3.5 nM). Weaker affinities were observed at alpha 1-adrenergic (K(i) = 43 nM), histamine H(1) (IC(50) = 30 nM), 5-HT(2A) (K(i) = 24.5 nM) and sigma (sigma) -1 binding sites (K(i) = 24.5 nM). In measures of in vitro functional activity, PD 158771 stimulated [(3)H]thymidine uptake in CHO p-5 cells transfected with hD(3) receptors with a maximal effect of 23% relative to quinpirole. In hD(2)L, the corresponding value was 60% with an EC(50) of 29 nM, again indicating partial DA agonist action of PD 158771. In vivo, PD 158771 produced a dose-related decrease in DA synthesis in the striatum and mesolimbic regions of rat brain treated with gamma-butyrolactone (GBL), indicating a DA autoreceptor agonist action. In animals not treated with GBL, PD 158771 produced a dose-related decrease in DA synthesis and extracellular DA. A decrease in 5-HT synthesis in several brain areas was observed consistent with an agonist response. Further support for DA autoreceptor agonist action is that PD 158771 produced a partial inhibition of the firing of substantia nigra zona compacta DA neurons, an effect reversed by haloperidol. In conclusion, PD 158771 exhibited affinities for DA and 5-HT receptors, appears to possess DA and 5-HT agonist actions; and it could provide improved antipsychotic profile with minimal side effects.