John B. Hogan

Donepezil primarily attenuates scopolamine-induced deficits in psychomotor function, with moderate effects on simple conditioning and attention, and small effects on working memory and spatial mapping

RationaleAlzheimer’s dementia (AD) patients have profound deficits in cognitive and social functions, mediated in part by a decline in cholinergic function. Acetylcholinesterase inhibitors (AChEI) are the most commonly prescribed treatment for the cognitive deficits in AD patients, but their therapeutic effects are small, and it is still not clear if they primarily affect attention, memory, or some other cognitive/behavioral functions.ObjectivesThe objective of the present experiments was to explore the effects of donepezil (Aricept™), an AChEI, on behavioral deficits related exclusively to cholinergic dysfunction.Materials and methodsThe effects of donepezil were assessed in Sprague–Dawley rats with scopolamine-induced deficits in a battery of cognitive/behavioral tests.ResultsScopolamine produced deficits in contextual and cued fear conditioning, the 5-choice serial reaction time test, delayed nonmatching to position, the radial arm maze, and the Morris water maze. Analyses of the pattern and size of the effects revealed that donepezil produced very large effects on scopolamine-induced deficits in psychomotor function (∼20–50% of the variance), moderate-sized effects on scopolamine-induced deficits in simple conditioning and attention (∼3–10% of the variance), but only small effects on scopolamine-induced deficits in higher cognitive functions of working memory and spatial mapping (∼1% of the variance).ConclusionsThese results are consistent with the limited efficacy of donepezil on higher cognitive function in AD patients, and suggest that preclinical behavioral models could be used not only to determine if novel treatments have some therapeutic potential, but also to predict more precisely what the pattern and size of the effects might be.

Scopolamine induced deficits in a battery of rat cognitive tests: comparisons of sensitivity and specificity.

Despite much research, the cognitive effects of scopolamine hydrobromide, a cholinergic antagonist, remain controversial. Scopolamine affects multiple systems each of which can impact behavior. One way to tease apart the effects of the drug is to determine the effects of low scopolamine doses on different abilities. The present experiments compared the effects of low doses of scopolamine on a single group of rats conducting a battery of behavioral tasks: Morris water maze, radial arm maze, delayed non-matching to position tasks, and fixed ratio 5 bar pressing. The behavioral battery ranged from tasks having little cognitive demand to those thought to be based more on attention and spatial-working memory. Control experiments using additional groups of rats assessing peripheral versus central effects were conducted with both liquid and dry reinforcement and with methyl scopolamine. Furthermore, the 5-choice serial reaction time test assessed scopolamine effects on attention. The data show a wide spectrum of central and peripheral cholinergic involvement. The central effects include attention and motor initiation, both of which impact and interact with the mnemonic function of acetylcholine. These results show that a limited disruption of the central cholinergic system can have profound effects on attention and/or psychomotor control before any measurable mnemonic disruption.

Pharmacological characterization and appetite suppressive properties of BMS-193885, a novel and selective neuropeptide Y1 receptor antagonist

Treatment of obesity is still a large unmet medical need. Neuropeptide Y is the most potent orexigenic peptide in the animal kingdom. Its five cloned G-protein couple receptors are all implicated in the regulation of energy homeostasis evidenced by overexpression or deletion of neuropeptide Y or its receptors. Neuropeptide Y most likely exerts its orexigenic activity via the neuropeptide Y(1) and neuropeptide Y(5) receptors, although the involvement of the neuropeptide Y(2) and neuropeptide Y(4) receptors are also gaining importance. The lack of potent, selective, and brain penetrable pharmacologic agents at these receptors made our understanding of the modulation of food intake by neuropeptide Y-ergic agents elusive. BMS-193885 (1,4-dihydro-[3-[[[[3-[4-(3-methoxyphenyl)-1-piperidinyl]propyl]amino] carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester) is a potent and selective neuropeptide Y(1) receptor antagonist. BMS-193885 has 3.3 nM affinity at the neuropeptide Y(1) receptor, acting competitively at the neuropeptide Y binding site. BMS-193885 increased the K(d) of [(125)I]PeptideYY from 0.35 nM to 0.65 nM without changing the B(max) (0.16 pmol/mg of protein) in SK-N-MC cells that endogenously express the neuropeptide Y(1) receptor. It is also found to be a full antagonist with an apparent K(b) of 4.5 nM measured by reversal of forskolin (FK)-stimulated inhibition of cAMP production by neuropeptide Y. Pharmacological profiling showed that BMS-193885 has no appreciable affinity at the other neuropeptide Y receptors, and is also 200-fold less potent at the alpha(2) adrenergic receptor. Testing the compound in a panel of 70 G-protein coupled receptors and ion channels resulted in at least 200-fold or greater selectivity, with the exception of the sigma(1) receptor, where the selectivity was 100-fold. When administered intracerebroventricularly or directly into the paraventricular nucleus of the hypothalamus, it blocked neuropeptide Y-induced food intake in rats. Intraperitoneal administration of BMS-193885 (10 mg/kg) also reduced one-hour neuropeptide Y-induced food intake in satiated rats, as well as spontaneous overnight food consumption. Chronic administration of BMS-193885 (10 mg/kg) i.p. for 44 days significantly reduced food intake and the rate of body weight gain compared to vehicle treated control without developing tolerance or affecting water intake. These results provide supporting evidence that BMS-193885 reduces food intake and body weight via inhibition of the central neuropeptide Y(1) receptor. BMS-193885 has no significant effect of locomotor activity up to 20 mg/kg dose after 1 h of treatment. It also showed no activity in the elevated plus maze when tested after i.p. and i.c.v. administration, indicating that reduction of food intake is unrelated to anxious behavior. BMS-193885 has good systemic bioavailability and brain penetration, but lacks oral bioavailability. The compound had no serious cardiovascular adverse effect in rats and dogs up to 30 and 10 mg/kg dose, respectively, when dosed intravenously. These data demonstrate that BMS-193885 is a potent, selective, brain penetrant Y(1) receptor antagonist that reduces food intake and body weight in animal models of obesity both after acute and chronic administration. Taken together the data suggest that a potent and selective neuropeptide Y(1) receptor antagonist might be an efficacious treatment for obesity in humans.

Effects of CRF1 receptor antagonists and benzodiazepines in the Morris water maze and delayed non-matching to position tests

RationaleBenzodiazepines continue to be widely used for the treatment of anxiety, but it is well known that benzodiazepines have undesirable side effects, including sedation, ataxia, cognitive deficits and the risk of addiction and abuse. CRF1 receptor antagonists are being developed as potential novel anxiolytics, but while CRF1 receptor antagonists seem to have a better side-effect profile than benzodiazepines with respect to sedation and ataxia, the effects of CRF1 receptor antagonists on cognitive function have not been well characterized. It is somewhat surprising that the potential cognitive effects of CRF1 receptor antagonists have not been more fully characterized since there is some evidence to suggest that these compounds may impair cognitive function.ObjectiveThe Morris water maze and the delayed non-matching to position test are sensitive tests of a range of cognitive functions, including spatial learning, attention and short-term memory, so the objective of the present experiments was to assess the effects of benzodiazepines and CRF1 receptor antagonists in these tests.ResultsThe benzodiazepines chlordiazepoxide and alprazolam disrupted performance in the Morris water maze and delayed non-matching to position at doses close to their therapeutic, anxiolytic doses. In contrast, the CRF1 receptor antagonists DMP-904 and DMP-696 produced little or no impairment in the Morris water maze or delayed non-matching to position test even at doses 10-fold higher than were necessary to produce anxiolytic effects.ConclusionsThe results of the present experiments suggest that, with respect to their effects on cognitive functions, CRF1 receptor antagonists seem to have a wider therapeutic index than benzodiazepines.

Soluble Aβ and cognitive function in aged F-344 rats and Tg2576 mice

Recent findings suggest that Alzheimers dementia may be mediated by soluble beta amyloid (Abeta) more than the deposits of aggregated, insoluble Abeta, and vulnerability to cognitive deficits after scopolamine challenge may help identify AD even in patients that are still pre-symptomatic. The objectives of the present experiments were to determine if vulnerability to cognitive deficits after scopolamine challenge is related to levels of soluble Abeta, and if levels of soluble Abeta are more closely related to cognitive deficits than levels of insoluble Abeta, even in aged, transgenic mice, after they have developed very high levels of insoluble Abeta. Aged F-344 rats and young mice over-expressing the Swedish mutation in the human amyloid precursor protein (APPsw; Tg2576+) had elevated levels of soluble Abeta, and were more vulnerable to scopolamine challenge in the Morris water maze (MWM), relative to young rats and Tg2576- mice; but, among individual animals, higher levels of soluble Abeta were not correlated with vulnerability to scopolamine. On the other hand, in aged Tg2576+ mice, cognitive deficits were related to levels of soluble Abeta, not insoluble Abeta, despite the fact that the levels of insoluble Abeta were thousands of times higher than the levels of soluble Abeta. The results of the present experiments suggest that vulnerability to cognitive deficits after scopolamine challenge is not related to elevated levels of soluble Abeta, but that high levels of soluble Abeta are more closely correlated with cognitive deficits than the amount insoluble Abeta, even after large amounts of aggregated, insoluble Abeta have been deposited.

Adverse effects of gabapentin and lack of anti-allodynic efficacy of amitriptyline in the streptozotocin model of painful diabetic neuropathy.

Amitriptyline and gabapentin are the primary treatments for painful diabetic neuropathy (PDN), and it is clear that they produce beneficial effects, but there are questions about these treatments that have not been adequately addressed. For example, although there is a growing consensus that the therapeutic effects of amitriptyline in pain patients are independent of its effects on mood, it is not clear that amitriptyline has specific and direct effects on pain. There is also a fairly broad consensus that gabapentin is safe and well tolerated, but the side-effect profile of gabapentin has not been adequately assessed in pain populations. The rat streptozotocin (STZ) model of PDN was used (a) to assess the effects of amitriptyline on objective, quantitative measures of tactile allodynia, a common type of pain in PDN patients, and (b) to assess the side effects of gabapentin using measures of motor/ambulatory and cognitive function. Amitriptyline did not attenuate STZ-induced mechanical allodynia, even after chronic administration of high doses. Gabapentin produced robust anti-allodynic effects but also produced deficits in tests of motor/ambulatory and cognitive functions. The present experiments suggest that the beneficial effects of amitriptyline in PDN may not be a result of anti-allodynic efficacy and that gabapentin produces robust anti-allodynic effects but may also produce significant motor and cognitive deficits even at or near the lowest effective doses. These findings challenge the consensus opinions about these primary treatments for PDN and suggest that their therapeutic and adverse effects should be explored further in pain patients.

Discovery of a Novel Class of Bicyclo[3.1.0]hexanylpiperazines as Noncompetitive Neuropeptide Y Y1 Antagonists.

A novel class of bicyclo[3.1.0]hexanylpiperazine neuropeptide Y (NPY) Y1 antagonists has been designed and synthesized. Scatchard binding analysis showed these compounds to be noncompetitive with [(125)I]PYY binding to the Y1 receptor. The most potent member, 1-((1α,3α,5α,6β)-6-(3-ethoxyphenyl)-3-methylbicyclo[3.1.0]hexan-6-yl)-4-phenylpiperazine (2) had an IC50 = 62 nM and displayed excellent oral bioavailability in rat (% F po = 80), as well as good brain penetration (B/P ratio = 0.61). In a spontaneous nocturnal feeding study with male Sprague-Dawley rats, 2 significantly reduced food intake during a 12 h period.

Triazolopyridine ethers as potent, orally active mGlu2 positive allosteric modulators for treating schizophrenia

Triazolopyridine ethers with mGlu2 positive allosteric modulator (PAM) activity are disclosed. The synthesis, in vitro activity, and metabolic stability data for a series of analogs is provided. The effort resulted in the discovery of a potent, selective, and brain penetrant lead molecule BMT-133218 ((+)-7m). After oral administration at 10mg/kg, BMT-133218 demonstrated full reversal of PCP-stimulated locomotor activity and prevented MK-801-induced working memory deficits in separate mouse models. Also, reversal of impairments in executive function were observed in rat set-shifting studies at 3 and 10mg/kg (p.o.). Extensive plasma protein binding as the result of high lipophilicity likely limited activity at lower doses. Optimized triazolopyridine ethers offer utility as mGlu2 PAMs for the treatment of schizophrenia and merit further preclinical investigation.

Heterocyclic modification of a novel bicyclo[3.1.0]hexane NPY1 receptor antagonist.

A convergent synthesis route for the heterocyclic modification of a novel bicyclo[3.1.0]hexane NPY1 antagonist 2 was developed and the structure activity relationship of these modifications on NPY1 binding is reported. Two heterocyclic analogs 9 and 10 showed comparable Y1 binding potency to 2, but with improved aqueous solubility. Compound 9 demonstrated reduced spontaneous nocturnal food intake in a rat model when dosed ip. Compound 9 was also shown to be orally bioavailable and brain penetrable.