Steven Z. Whetzel
Pfizer
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Featured researches published by Steven Z. Whetzel.
Neuropharmacology | 2001
Hyacinth Akunne; Kim Zoski; Steven Z. Whetzel; J.J Cordon; R.M Brandon; F Roman; Thomas A. Pugsley
Igmesine is a selective sigma (sigma(1)) ligand that was reported to exert antidepressant action through an unknown mechanism of action. A number of neurochemical measures were taken in this study in efforts to understand its mode of action. Following 21-day drug treatments, the actions of igmesine on a number of neurochemical measures were investigated. Data obtained showed significant decreases in the densities of beta-adrenergic but not 5-HT(1A), sigma(1) and GABA(B) receptors in fluoxetine (18%), desipramine (DMI, 32%) and igmesine (20%)-treated groups when compared with control. Tyrosine hydroxylase (TH) activity was significantly (30-32%) reduced in all treated groups. Further, fluoxetine and DMI excluding the igmesine-treated groups showed 85 and 40% reductions in serotonin (5-HT) and noradrenaline (NE) neuronal uptake, respectively. Following acute treatment, igmesine lacked activity for monoamine oxidase (MAO) A or B (IC(50)>10 microM). In in vivo studies, at behaviorally active doses, igmesine showed weak effects on the NE uptake but lacked activity in altering 5-HT and DA synthesis or antagonizing selective drug-induced depletion of monoamine neuronal uptake. N-methyl-D-aspartate (NMDA)-induced increases in cGMP was blocked by igmesine indicating that igmesine may interfere with the NMDA receptor/nitric oxide synthase/cGMP pathway. Although it appears that part of the pharmacological actions of igmesine is mediated by the monoaminergic system, there is still need to explore other possible mechanisms of antidepressant action.
Bioorganic & Medicinal Chemistry Letters | 2011
Douglas S. Johnson; Chung Choi; Lorraine Kathleen Fay; David A. Favor; Joseph Thomas Repine; Andrew David White; Hyacinth Akunne; Lawrence W. Fitzgerald; Kim Nicholls; Bradley Snyder; Steven Z. Whetzel; Liming Zhang; Kevin A. Serpa
The synthesis and structure-activity relationship (SAR) of a novel series of aryl piperazine napthyridinone D(2) partial agonists is described. Our goal was to optimize the affinities for the D(2), 5-HT(2A) and 5-HT(1A) receptors, such that the D(2)/5-HT(2A) ratio was greater than 5 to ensure maximal occupancy of these receptors when the D(2) occupancy reached efficacious levels. This strategy led to identification of PF-00217830 (2) with robust inhibition of sLMA (MED=0.3mg/kg) and DOI-induced head twitches in rats (31% and 78% at 0.3 and 1mg/kg) with no catalepsy observed at the highest dose tested (10 mg/kg).
Progress in Neuro-psychopharmacology & Biological Psychiatry | 2002
Thomas A. Pugsley; Yu Hsin Shih; Steven Z. Whetzel; Kim Zoski; Don Van Leeuwen; Hyacinth Akunne; Robert MacKenzie; Thomas G. Heffner; David Juergen Wustrow; Lawrence D. Wise
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.
Neuropharmacology | 2000
Hyacinth Akunne; Kim Zoski; Michael Duff Davis; L. W. Cooke; L. T. Meltzer; Steven Z. Whetzel; Y. H. Shih; David Juergen Wustrow; Lawrence D. Wise; Robert MacKenzie; Lynn M. Georgic; Thomas G. Heffner; Thomas A. Pugsley
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.
Journal of Pharmacology and Experimental Therapeutics | 1995
Thomas A. Pugsley; Davis; Hyacinth Akunne; Rg MacKenzie; Yh Shih; G Damsma; H Wikstrom; Steven Z. Whetzel; Lynn M. Georgic; Lw Cooke; Sb Demattos; Ann E. Corbin; Shelly Ann Glase; Lawrence D. Wise; D Dijkstra; Thomas G. Heffner
Synapse | 2002
David J. Dooley; Cindy M. Donovan; Wolfgang P. Meder; Steven Z. Whetzel
Journal of Medicinal Chemistry | 1998
David Juergen Wustrow; Thomas Richard Belliotti; Shelly Ann Glase; Suzanne Ross Kesten; Don Johnson; Norman L. Colbry; Ronald Rubin; Anthony C. Blackburn; Hyacinth Akunne; Ann E. Corbin; M. Duff Davis; Lynn M. Georgic; Steven Z. Whetzel; Kim Zoski; Thomas G. Heffner; Thomas A. Pugsley; Lawrence D. Wise
Journal of Medicinal Chemistry | 1999
Thomas Richard Belliotti; David Juergen Wustrow; Wouter A. Brink; Kim Zoski; Yu-Hsin Shih; Steven Z. Whetzel; Lynn M. Georgic; Ann E. Corbin; Hyacinth Akunne; Thomas G. Heffner; Thomas A. Pugsley; Lawrence D. Wise
Journal of Medicinal Chemistry | 1997
David Juergen Wustrow; William J. Smith; Ann E. Corbin; M. Duff Davis; Lynn M. Georgic; Thomas A. Pugsley; Steven Z. Whetzel; Thomas G. Heffner; Lawrence D. Wise
Journal of Pharmacology and Experimental Therapeutics | 1995
Thomas A. Pugsley; M. D. Davis; Hyacinth Akunne; L. W. Cooke; Steven Z. Whetzel; Robert MacKenzie; Y. H. Shih; D. H. Van Leeuwen; S. B. Demattos; L. M. Georgic; B. W. Caprathe; J. C. Wright; J. C. Jaen; Lawrence D. Wise; Thomas G. Heffner