Broad-spectrum, non-opioid analgesic activity by selective modulation of neuronal nicotinic acetylcholine receptors.

Development of analgesic agents for the treatment of severe pain requires the identification of compounds that are devoid of opioid receptor liabilities. A potent (inhibition constant = 37 picomolar) neuronal nicotinic acetylcholine receptor (nAChR) ligand called ABT-594 was developed that has antinociceptive properties equal in efficacy to those of morphine across a series of diverse animal models of acute thermal, persistent chemical, and neuropathic pain states. These effects were blocked by the nAChR antagonist mecamylamine. In contrast to morphine, repeated treatment with ABT-594 did not appear to elicit opioid-like withdrawal or physical dependence. Thus, ABT-594 may be an analgesic that lacks the problems associated with opioid analgesia.

Inhibition of insulin release from rat pancreatic islets by drugs that are analogues of dopamine.

Various synthetic dopamine (DA) analogues have been shown to produce glucose intolerance and inhibit the compensatory increase in serum insulin during an oral glucose tolerance test (OGTT). To investigate the possibility that there is a direct action of dopamine analogues to inhibit glucose-stimulated insulin release from the endocrine pancreas, the following compounds were compared with the effects of epinephrine (EPI) on isolated rat pancreatic islets: apomorphine (APO), pergolide, lergotrile, TL-99 (2-dimethylamino-6,7-dihydroxytetralin), and RDS-127 (2-di-n-propyl-amino-4,7-dimethoxyindane). EPI, TL-99, and pergolide inhibited insulin release in a concentration-dependent fashion (10(-7)-10(-5) M), whereas lergotrile inhibited at 10(-5) M but not at 10(-6) M. RDS-127 and APO were ineffective at 10(-5) M, but produced a greater than 50% inhibition at 2 X 10(-4) M. The potencies of the DA analogues fell into two groups: compounds that are approximately as active as EPI (e.g., TL-99 and pergolide) or compounds that are relatively inactive (e.g., APO, lergotrile, and RDS-127). The inhibitory actions of EPI, TL-99, and pergolide were blocked by the alpha 2-adrenergic receptor antagonist yohimbine, whereas the DA receptor antagonist, sulpiride, had no effect, suggesting an action initiated at alpha 2-adrenergic receptors. Drugs from both groups produced marked glucose intolerance and inhibited the compensatory increase in insulin during an OGTT. Adrenodemedullation blocked the glucose intolerance and inhibition of insulin release caused by RDS-127, whereas these effects of TL-99 were not attenuated.(ABSTRACT TRUNCATED AT 250 WORDS)

Cortical cerebral blood flow governed by the basal forebrain: age-related impairments.

This study sought to compare resting and evoked increases in cortical microvascular perfusion elicited by electrical microstimulation of the basal forebrain (BF) in young (4-6 months) and aged (22-26 months) Sprague-Dawley rats. Regional cerebral blood flow (rCBF) was measured in chloralose-anesthetized rats for twelve bilateral regions using 14C-iodoantipyrine with regional brain dissection, while second-to-second changes in tissue perfusion were concurrently assessed using laser-doppler flowmetry (LDF). In young animals, BF stimulation elicited significant ipsilateral increases in CBF in parietal (+123%) and frontal (+107%) cortices, caudate nucleus (+63%) and thalamus (+59%) (p less than 0.05). The BF-elicited increases were preserved in frontal cortex and thalamus, but not in parietal cortex or caudate nucleus of aged animals. No frequency- or current-specific attenuations were observed in the spared frontal cortex of aged animals. However, there was a significant (+70%) age-related increase in the latency to reach maximal blood flow increases (p less than 0.05), without any change in the total time of increased blood flow. These findings support the hypothesis that cortical CBF is in part governed by BF neurons, and suggest that regionally selective, age-related impairments of cortical coupling of neuronal to dynamic vascular responses exist. It remains to be determined whether the mechanism of this impairment relates to an age-related impairment in coupling of blood flow and metabolism.

Cloning and transient expression of genes encoding the human alpha 4 and beta 2 neuronal nicotinic acetylcholine receptor (nAChR) subunits.

Partial cDNA clones generated by RT-PCR were used as probes to clone the cDNAs encoding the human alpha 4 and beta 2 neuronal nicotinic acetylcholine receptor (nAChR) subunits. The 2.1-kb alpha 4 cDNA shows 84 and 76% identity to the rat and chicken cDNA sequences, respectively. The deduced amino-acid sequence shares 89 and 84% similarity, respectively, with the corresponding rat and chicken proteins, with most of the divergence occurring in the cytoplasmic domain. The 1721-nucleotide beta 2 sequence was identical to the human beta 2 sequence previously reported. Transfection of the alpha 4 and beta 2 clones into HEK293 cells resulted in the formation of binding sites that display high affinity towards [3H] cytisine, a characteristic of the alpha 4 beta 2 subtype produced in vivo.

Potent anorexic-like effects of RDS-127 (2-di-n-propylamino-4,7-dimethoxyindane) in the rat: a comparison with other dopamine-receptor agonists.

Modification of food intake and motor activity was investigated following administration of amphetamine (AMP), apomorphine (APO) and three novel 2-aminoindanes (2-AI): 2-di-n-propylaminoindane (JPC-60-36), 2-di-n-propylamino-5,6-dimethoxyindane (JPC-211) and 2-di-n-propylamine-4,7-dimethoxyindane (RDS-127). These compounds demonstrated dose- and time-related inhibition of food intake in male rats which were habituated to eating 4 hr each day. The ranked potencies were as follows: RDS-127 greater than AMP = APO greater than JPC-60-36 and JPC-211 was inactive. 2-di-n-Propylamine-4,7-dimethoxyindane (RDS-127) did not increase motor activity in a dose range that Significantly inhibited food intake (66% of control intake with 0.08 mumol/kg). Food intake inhibition was blocked by pimozide, but not by propranolol or phentolamine. The anorectic-like actions of RDS-127 were long-lasting (greater than 4 hr) and RDS-127 was approximately 3-fold more potent than amphetamine or apomorphine in producing increased locomotor activity; the other 2-aminoindanes were less potent in producing hyperactivity. Hyperactivity responses were blocked by pimozide, but not by alpha-methyl-p-tyrosine. These results suggest that 2-aminoindanes may modify motor behaviors, at least in part, via direct stimulation of dopamine receptors. The structure-activity relationships of 2-aminoindanes on locomotor activity and inhibition of food intake are discussed.

Is domperidone a selective peripheral dopamine-receptor antagonist in vivo?

The ability of domperidone (DOM) to antagonize dopamine (DA) receptor agonist-induced hypothermia or hyperactivity was investigated in rats. Apomorphine (APO) or RDS-127 (2-di-n-propylamino-4,7-dimethoxyindane), two DA receptor agonists, produced dose-dependent hypothermia following subcutaneous (s.c.) administration. Also, RDS-127 produced hypothermia following lateral ventricular (i.c.v.) administration. The hypothermia produced by apomorphine or RDS-127 (given s.c. or i.c.v.) was antagonized by pretreatment with pimozide (0.25 mg/kg, i.p.) or domperidone (0.2, 1.0 and 5.0 mg/kg, i.p.). The hyperactivity produced by apomorphine was unaffected by pretreatment with domperidone. These data suggested that central DA receptors mediating temperature regulation, but not those mediating locomotor activity are accessible to peripherally administered domperidone. Therefore, domperidone may not be useful to differentiate hypothalamic (central) vs peripheral sites of action for DA receptor agonists in the rat.

Evidence that central dopamine receptors modulate sympathetic neuronal activity to the adrenal medulla to alter glucoregulatory mechanisms.

Previous reports suggest that analogs of dopamine (DA) can produce hyperglycemia in rats by interacting with DA receptors. Experiments reported here indicate the site of action and describe the metabolic sequalae associated with the hyperglycemic effect of apomorphine (APO), produced in conscious unrestrained rats. Apomorphine was more potent when administered by intracerebroventricular (i.c.v.) injection than when given subcutaneously (s.c.). Very small doses of the DA receptor antagonist pimozide, given intraventricularly, blocked the hyperglycemic effect of apomorphine administered subcutaneously. Sectioning of the spinal cord at thoracic vertebra T1-2 or sectioning the greater splanchnic nerve blocked apomorphine-induced hyperglycemia; whereas section of the superior colliculus or section at T5-6 had no effect. A dose of apomorphine or epinephrine (EPI) producing a similar degree of hyperglycemia elevated the concentration of EPI in serum to a similar degree, and the increase in EPI in serum preceded the increase in glucose in serum. Fasting animals for 2 or 18 hr had no significant effect on EPI- or apomorphine-induced hyperglycemia despite a reduction (91-93%) of the glycogen content of liver and skeletal muscle during the 18 hr fast. 5-Methoxyindole-2-carboxylic acid (MICA), an inhibitor of gluconeogenesis, blocked EPI- and apomorphine-induced hyperglycemia in rats fasted for 18 hr. However, 5-methoxyindole-2-carboxylic acid was ineffective in blocking hyperglycemia in animals fasted for 2 hr. Changes in insulin or glucagon in serum alone cannot account for the hyperglycemic action of apomorphine. These data demonstrate that apomorphine interacts with central DA receptors located in the hindbrain to activate sympathetic neuronal activity to the adrenal gland which subsequently releases epinephrine to alter homeostasis of glucose. Epinephrine may then, depending on the nutritional status, facilitate glycogenolytic or gluconeogenic processes to produce hyperglycemia.

A-85380 [3-(2(S)-azetidinylmethoxy) pyridine]: in vitro pharmacological properties of a novel, high affinity alpha 4 beta 2 nicotinic acetylcholine receptor ligand.

The in vitro pharmacological properties of a novel cholinergic channel ligand, A-85380 [3-(2(S)-azetidinylmethoxy)pyridine], were examined using tissue preparations that express different putative nAChR subtypes. In radioligand binding studies, A-85380 is shown to be a potent and selective ligand for the human alpha 4 beta 2 nAChR subtype (Ki = 0.05 + 0.01 nM) relative to the human alpha 7 (Ki = 148 +/- 13 nM) and the muscle alpha 1 beta 1 dg subtype expressed in Torpedo electroplax (Ki = 314 +/- 12 nM). The R-enantiomer of A-85380, A-159470, displays little enantioselectivity towards the alpha 4 beta 2 and alpha 1 beta 1 delta gamma subtypes but does not display 12-fold enantioselectivity towards the alpha 7 subtype (Ki = 1275 +/- 199 nM). (+)- and(-)-Epibatidine display similar potencies at the human human alpha 4 beta 2 (Ki = 0.04 +/- 0.02 nM and 0.07 +/- 0.02 nM, respectively), human alpha 7 (Ki = 16 +/- 2 nM and 22 +/- 3 nM, respectively) and muscle alpha 1 beta 1 delta gamma g (Ki = 2.5 +/- 0.9 nM and 5.7 +/- 1.0 nM, respectively) nAChRs. Functionally, A-85380 is a potent activator of cation efflux through the human alpha 4 beta 2 (EC50 = 0.7 +/- 0.1 microM) and ganglionic (EC50 = 0.8 +/- 0.09 microM) subtypes, effects that are attenuated by pretreatment with mecamylamine (10 microM). Further, A-85380 can activate (EC50 = 8.9 +/- 1.9 microM) currents through channels formed by injection of the human alpha 7 subunit into Xenopus oocytes, effects that are attenuated by pretreatment with the alpha 7 nAChR antagonist, methyllycaconitine (10 nM). In all cases, A-85380 is more potent than (-)-nicotine but less potent than (+/-)-epibatidine. In neurotransmitter release studies, A-85380 stimulates the release of dopamine with an EC 50 value of 0.003 +/- 0.001 microM which is equipotent to (+/-)-epibatidine, and 20-fold more potent than (-)-nicotine (EC50 = 0.04 +/- 0.009 microM). Thus, A-85380 displays a profile of robust activation of a number of nAChR subtypes with substantially less affinity for [125I] alpha-BgT sites than [3H](-)-cytisine sites, suggesting that it may serve as a more selective pharmacologic probe for the alpha 4 beta 2 subtype relative to the alpha 7 and alpha 1 beta 1 delta g nAChRs than (+/-)-epibatidine.

2-Amino-4,7-dimethoxyindan derivatives: synthesis and assessment of dopaminergic and cardiovascular actions.

N-Alkylated derivatives of 2-amino-4,7-dimethoxyindan were prepared for evaluation of central and peripheral dopaminergic activity using biochemical and behavioral tests in the rat and cardiovascular responses in the cat. 2-(Di-n-propylamino)-4,7-dimethoxyindan (4e) demonstrated equal activity with apomorphine to activate peripheral presynaptic dopamine receptors. Central pre- and postsynaptic dopamine receptors were also activated with 4e. In contrast to the intense long-acting sympathomimetic actions previously reported for the 2-amino-5,8-dimethoxytetralins, these compounds produced weak, transient effects in heart rate and blood pressure. The majority of 2-amino-4,7-dimethoxyindan derivatives tested are weak or inactive pre- and postsynaptic dopamine receptor agonists.

Novel 3-Pyridyl ethers with subnanomolar affinity for central neuronal nicotinic acetylcholine receptors.

Recent evidence indicating the therapeutic potential of cholinergic channel modulators for the treatment of central nervous system (CNS) disorders as well as the diversity of brain neuronal nicotine acetylcholine receptors (nAChRs) have suggested an opportunity to develop subtype-selective nAChR ligands for the treatment of specific CNS disorders with reduced side effect liabilities. We report a novel series of 3-pyridyl ether compounds which possess subnanomolar affinity for brain nAChRs and differentially activate subtypes of neuronal nAChRs. The synthesis and structure-activity relationships for the leading members of the series are described, including A-85380 (4a), which possesses ca.50 pM affinity for rat brain [(3)H]-(-)-cytisine binding sites and 163% efficacy compared to nicotine to stimulate ion flux at human alpha4beta2 nAChR subtype, and A-84543 (2a), which exhibits 84-fold selectivity to stimulate ion flux at human alpha4beta2 nAchR subtype compared to human ganglionic type nAChRs. Computational studies indicate that a reasonable superposition of a low energy conformer of 4A with (S)-nicotine and (-)-epibatidine can be achieved.

Structure-activity studies on 2-methyl-3-(2(S)-pyrrolidinylmethoxy) pyridine (ABT-089): an orally bioavailable 3-pyridyl ether nicotinic acetylcholine receptor ligand with cognition-enhancing properties.

2-Methyl-3-(2(S)-pyrrolidinylmethoxy)pyridine, ABT-089 (S-4), a member of the 3-pyridyl ether class of nicotinic acetylcholine receptor (nAChR) ligands, shows positive effects in rodent and primate models of cognitive enhancement and a rodent model of anxiolytic activity and possesses a reduced propensity to activate peripheral ganglionic type receptors. The profiles of S-4, its N-methyl analogue, and the corresponding enantiomers across several measures of cholinergic channel function in vitro and in vivo are presented, together with in vitro metabolism and in vivo bioavailability data. On the basis of its biological activities and favorable oral bioavailability, S-4 is an attractive candidate for further evaluation as a treatment for cognitive disorders.

Identification and initial structure-activity relationships of (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), a potent, orally active, non-opiate analgesic agent acting via neuronal nicotinic acetylcholine receptors.

New members of a previously reported series of 3-pyridyl ether compounds are disclosed as novel, potent analgesic agents acting through neuronal nicotinic acetylcholine receptors. Both (R)-2-chloro-5-(2-azetidinylmethoxy)pyridine (ABT-594, 5) and its S-enantiomer (4) show potent analgesic activity in the mouse hot-plate assay following either intraperitoneal (i.p.) or oral (p.o.) administration, as well as activity in the mouse abdominal constriction (writhing) assay, a model of persistent pain. Compared to the S-enantiomer and to the prototypical potent nicotinic analgesic agent (+/-)-epibatidine, 5 shows diminished activity in models of peripheral side effects. Structure-activity studies of analogues related to 4 and 5 suggest that the N-unsubstituted azetidine moiety and the 2-chloro substituent on the pyridine ring are important contributors to potent analgesic activity.

Maintenance of local cerebral blood flow after acute neuronal death: possible role of non-neuronal cells.

In brain, a major factor regulating local perfusion is local neuronal activity. However, we have recently discovered that, in rat, five days after selective neuronal destruction in the parietal cortex by local microinjections of the excitotoxin ibotenic acid, local cerebral blood flow, within the lesion, remains in the normal range. We studied whether proliferating non-neuronal cells and/or local changes in microvascular density participate to maintain local cerebral blood flow. Rats were anesthetized (halothane 1-3%), ibotenic acid (10 micrograms in 1 microliter) was locally microinjected in a restricted region of the parietal cortex, and animals were allowed to recover. Three, five, seven, 11, 30 days later local cerebral blood flow was measured autoradiographically under chloralose anesthesia (40 mg/kg, s.c.) by the [14C]iodoantipyrine technique. Cellular density or microvascular area were determined on sections stained with Thionine or processed for the endothelial marker alkaline phosphatase, respectively. Local neurons were destroyed by 24 h after microinjections of ibotenic acid. However, from three to 11 days after lesion local cerebral blood flow was unchanged (P greater than 0.05; n = 5), thereafter declining so that by 30 days blood flow was 48 +/- 6% of control (P less than 0.05; n = 5). Cellular density increased within the lesion by 17.5-fold at seven to 11 days (P less than 0.01) and declined to a 11.7-fold elevation above control at day 30 (P less than 0.01). New cells consisted of macrophages, endothelium and glial fibrillary acidic protein-positive astrocytes. The microvascular area increased 4.2-fold from three to 11 days (P less than 0.01). The patency of the presumably newly formed vessels was determined by the presence of intravascular red blood cells, which were revealed histochemically. The area occupied by red blood cells within cerebral microvessels, in contrast to microvascular area, did not increase until seven days after lesion, reaching a 3.2-fold increase at 11 days. Thus within the lesion, local cerebral blood flow remains constant during the phase in which cellular and microvascular density increases. The presumably newly formed vessels cannot contribute to maintain local cerebral blood flow since during this phase they are not patent; rather patency develops coincident with the decline in local cerebral blood flow. We conclude that non-neuronal cells, most likely activated macrophages, may be an important factor regulating local cerebral perfusion, after acute neuronal death.

Thyroid hormone regulation of NGF, NT-3 and BDNF RNA in the adult rat brain.

The effects of peripherally administered thyroid hormone (TH; 500 micrograms/kg; i.p.; q.d.) on the relative abundances of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) RNA were determined by rtPCR in the cortex and hippocampus of young adult rats. Corresponding changes in choline acetyltransferase (ChAT) activity were measured since NGF and BDNF have been shown to enhance the expression of this marker enzyme of central cholinergic pathways. Abundance levels of NGF and NT-3, relative to cyclophilin (cycl), were increased significantly (+50%, P < 0.05) in the hippocampus following TH treatment. Despite enhanced abundance of NGF in the hippocampus, ChAT activity was unchanged, whereas ChAT activity was modestly increased by 28% in the cortex without corresponding changes in NGF, NT-3 or BDNF. These results demonstrate that TH administration is capable of inducing the accumulation of NT-3, in addition to NGF but that the induction levels of RNA cannot be directly correlated with responsivity of the cholinergic system as measured by ChAT activity.

Attenuation of fear conditioning by antisense inhibition of brain corticotropin releasing factor-2 receptor.

Corticotropin releasing factor (CRF) is an important regulator of the endocrine, behavioral, autonomic and immune responses to stress. Two high affinity CRF receptors have been identified, which are distributed in distinct anatomical regions. CRF(1) receptors have been relatively well characterized and antagonists to this receptor effectively block stress-induced behaviors in rodents. The function of CRF(2) receptors, which are highly expressed in limbic brain regions, is less well understood. Therefore, an antisense oligonucleotide approach was used to study the role of CRF(2) receptors in the lateral septum in rats. An antisense oligonucleotide directed against the CRF(2) receptor mRNA reduced expression of CRF(2) receptors by 60--80%. In shock-induced freezing tests, animals administered the antisense oligonucleotide exhibited a significant reduction in freezing duration. However, pain sensitivity and locomotor activity were unaltered. A four-base mismatch of the antisense sequence had no significant effects on CRF(2) receptor density and on freezing behavior. These data support the involvement of CRF(2) receptors in fear conditioning. CRF(1) receptor antagonists also reduce freezing in this test. Additional studies to determine the effects of simultaneous inhibition of both receptor subtypes show that rats receiving both CRF(2) receptor antisense oligonucleotide and CRF(1) receptor antagonist froze significantly less than animals treated with either agent alone. These results provide additional evidence for the role of CRF(2) receptors in mediating the stress-induced actions of endogenous CRF.

Effects of ovariectomy, castration, and chronic lithium chloride treatment on stereotyped behavior in rats.

The effects of ovariectomy, castration, and chronic lithium chloride treatment on stereotyped behavior (SB) induced by apomorphine (APO) (0.3--0.6 mg/kg) were investigated in rats. Duration of stereotyped behavior (interval between APO injection and termination of SB) increased in ovariectomized rats compared to female control rats. Castration had no effect on the duration of stereotyped behavior. On the other hand, ovariectomized rats that were treated chronically with LiCl (2mEq/kg daily) showed no difference in duration of stereotyped behavior compared to female controls chronically treated with LiCl. Neither treatment group showed a significantly altered intensity of stereotyped behavior compared with the appropriate control. These findings are consistent with the hypothesis that estrogen deficit contributes to a greater incidence of neuroleptic-induced tardive dyskinesia in postmenopausal women than in men of comparable age. Furthermore, LiCl may attenuate the symptoms associated with increased postsynaptic dopamine receptor sensitivity following ovariectomy.

ABT-418: discriminative stimulus properties and effect on ventral tegmental cell activity.

Previous studies have established that ABT-418 [(S)-3-methyl-5-(1 methyl-2-pyrrolidinyl)isoxazole hydrochloride] is a novel neuronal nicotinic acetylcholine receptor (nAChR) ligand with cognitive enhancing and anxiolytic-like activity 3- to 10-fold more potent than (-)-nicotine in rodents. A series of experiments was conducted to determine the discriminative stimulus properties of ABT-418 in comparison with (-)-nicotine, and to determine the relative potencies of these compounds on ventral tegmental area (VTA) neurons. While rats were able to discriminate (-)-nicotine 1.9 mumol/kg in 39 days, they were not able to discriminate 1.9 or 6.2 mumol/kg ABT-418 from a saline solution during 50 days of training. In rats trained to discriminate 1.9 mumol/kg (-)-nicotine, a reduced generalization was induced by ABT-418 at 1.9 and 6.2 mumol/kg, an effect completely blocked by the cholinergic channel blocker mecamylamine (15 mumol/kg, IP). However, in extensively trained rats, intraperitoneal or subcutaneous injections of ABT-418 induced 78-82% generalization at the 6.2 mumol/kg dose. The predominant metabolites of (-)-nicotine and ABT-418 (continine and A-87770, respectively) were devoid of any effect in nicotine-trained rats. The reduced potency of ABT-418 in nicotine-trained rats is consistent with the electrophysiological findings showing that ABT-418 is 3-fold less potent than (-)-nicotine in activating dopamine-containing neurons in the VTA area.

Improvement in accuracy of delayed recall in aged and non-aged, mature monkeys after intramuscular or transdermal administration of the CNS nicotinic receptor agonist ABT-418.

ABT-418 was evaluated for its ability to enhance accuracy on a delayed matching-to-sample (DMTS) task by aged monkeys following intramuscular administration, and in non-aged mature monkeys following transdermal application. Aged monkeys were impaired in their performance of the DMTS task such that the longest delay intervals performed at above-chance levels extended only to 20 s. In contrast, for non-aged, mature animals, delay intervals extended to 140 s. In aged monkeys, the response to ABT-418 was highly individualized with animals responding to one or more doses in the range of 2-259 nmol/kg. A systematic dose-dependent enhancement of DMTS accuracy was not observed. When the individualized "best dose" was administered on a separate occasion, overall DMTS accuracy was increased by 12.6%. By 24 h after administration, accuracy was at control levels. In young monkeys, a significant dose-dependent enhancement of DMTS performance (an overall increase of 11.25% above baseline accuracy) was observed 5 h after application of a transdermal patch designed to maintain steady-state plasma levels of ABT-418 of 40-60 ng/ml over a 24-h period. Again there was some individual responsiveness to one of the three doses. When data included only the individualized best doses of ABT-418 for each animal, a similar enhancement of accuracy was observed for both the 5-h and 24-h test intervals. In neither the aged nor the young cohorts was enhancement of performance associated with altered response latencies or with any overt side effects of ABT-418. Thus, these data are consistent with the ability of ABT-418 to improve DMTS performance in both young and aged monkeys. In aged monkeys, this response was observed only after administration of individualized optimal doses for different monkeys. In young monkeys, a more systematic enhancement of DMTS accuracy was observed. Further, transdermal delivery of ABT-418 in non-aged monkeys demonstrated prolonged performance enhancement compared with IM injection to at least 24 h after patch administration.

Central nicotinic receptor agonists ABT-418, ABT-089, and (-)-nicotine reduce distractibility in adult monkeys.

Increased distractibility is associated with both Alzheimer's disease and attention deficit disorder. The present study examined the effects of (-)-nicotine and the novel central nicotinic receptor (nAChR) agonists ABT-418 [(S)-3-methyl-2-pyrrolidinyl)isoxazole] and ABT-089 [2-methyl-3-(2-(S)-pyrrolindinylmethoxy)pyridine dihydrochloride] on the delayed recall accuracy of adult monkeys exposed to distracting stimuli. Unpredictable exposure to a random visual array produced marked decrements in recall accuracy on trials with the shortest delay intervals, reducing the accuracy on these trials by 23.4%. Intramuscular (i.m.) administration of (-)-nicotine, in doses of 5.4-43.3 nmol/kg, attenuated the effect of the distractor, but did not completely prevent it. Both ABT-418 (2.0-16.2 nmol/kg, i.m.) and ABT-089 (16.4-32.8 nmol/kg, i.m.) prevented distractibility, producing increases of 7.5-25.0% in accuracy on trials disrupted by distractor exposure. Further, both compounds also improved accuracy on trials during which distractors were not presented, an effect which was not observed after (-)-nicotine administration. Nicotinic-mediated side effects were not observed following administration of any compound. Thus, nAChR stimulation reduces distractibility in adult monkeys and may, therefore, represent a target for the pharmacologic treatment of disorders associated with susceptibility to distraction. ABT-418 and ABT-089 appear to be particularly useful in this regard, a likely result of their selective agonist activity at nAChRs expressed in the brain.

Improvement in performance of a delayed matching-to-sample task by monkeys following ABT-418: a novel cholinergic channel activator for memory enhancement.

ABT-418, a newly characterized centrally acting cholinergic channel activator (ChCA), was evaluated for its ability to improve performance in a delayed matching-to-sample (DMTS) task by mature macaques well trained in the task. Previous studies in rodents have indicated that ABT-418 shares the memory/cognitive enhancing actions of nicotine, but without many of nicotine's dose-limiting side effects. As DMTS provides a measure both of general cognitive function (the matching concept) and of recent memory, it was hypothesized that some doses of ABT-418 would enhance the monkeys' ability to correctly perform the DMTS task. Intramuscular administration of ABT-418 significantly enhanced DMTS performance at low (2-32.4 nmol/kg) doses. In fact, the drug was slightly more potent that nicotine in this regard, and all eight animals tested in this study exhibited enhanced performance at one or more doses. ABT-418 produced the greatest improvement in DMTS performance at the longest delay interval. In animals repeatedly tested with their individualized "Best Dose", DMTS performance increased on average by 10.1 +/- 3.5 percentage points correct, which was equivalent to an increase of 16.2% over baseline performance. ABT-418 did not significantly affect response times, i.e., latencies to make a choice between stimuli, or latencies to initiate new trials. Whereas nicotine enhanced DMTS performance both on the day of administration and on the following day (in the absence of drug), ABT-418-induced enhanced performance was detected only on the day of administration. Finally, single daily administration of the individualized best dose in three monkeys over a period of 8 days generally maintained enhancement of DMTS performance. Thus, the data were not consistent with the development of significant tolerance to the drug's mnemonic actions. In contrast to nicotine, no overt toxicity or side effects to acute or repeated administration of the drug were noted. Thus, ABT-418 represents a prototype of a new class of nicotinic agonists designed for the potential treatment of human dementias having a low profile of toxicity.