Biomedical subjects

M F Piercey

Publications and source records attributed to M F Piercey.

At least 37 records · Page 2Linked to original sources

PubMed1994

Metabolic effects of scopolamine and physostigmine in human brain measured by positron emission tomography.

Two of the more consistent findings in Alzheimer's disease are depressions in frontal and temporoparietal glucose metabolism and a loss of cholinergic neurons in the nucleus basalis of Meynert. Nonetheless, cholinergic replacement strategies have had only minimal therapeutic successes. Whether this situation reflects the limited contribution of cholinergic deafferentation to the intellectual decline or the meager ability of the pharmaceuticals tested to exert their intended pharmacologic action remains unclear. To address this question, the distribution of cerebral abnormalities found in untreated Alzheimer patients, as revealed by positron emission tomography following 18F-fluorodeoxyglucose, were compared with the pattern of functional changes produced by drugs that block or stimulate cholinergic function. Physostigmine was administered to 6 Alzheimer patients to increase brain cholinergic neurotransmission. The anticholinergic scopolamine, given to normal volunteers, was administered to 6 age-matched controls. These data were compared to those obtained from the same subjects while receiving placebo. Amnestic doses of the anticholinergic, scopolamine increased glucose metabolism by up to 20% (p < 0.001) in all brain regions studied, except thalamus. This response contrasted with the metabolic reductions of up to 17% (p < 0.01), especially in parietal and frontal association cortices, occurring in unmedicated Alzheimer patients. Maximum tolerated doses of the anti-cholinesterase, physostigmine, rather than tending to normalize abnormalities in these patients, further reduced cerebral metabolism (p < 0.01) and increased metabolism in thalamus in a pattern inversely correlated (p < 0.001) with that produced by scopolamine. These results fail to support a cholinergic basis for the abnormal metabolic pattern in Alzheimer's disease.

Aged↗

PubMed1994

Imaging brain function in animals to understand drugs of abuse and potential pharmacotherapies.

Brain imaging studies can be used to enhance current understanding of how CNS drugs act. Because the brain is in reality a collection of independent, albeit interconnected, neural organs, identification of sites of brain action are critical to an appraisal of how each drug exerts its different behavioral and physiological effects. For new drugs not yet tested in humans, identification of which neuronal structures are affected by a drug can give clues as to what to expect from the drug if it is eventually exposed to clinical testing. Receptor binding autoradiography, more than any other technique, pinpoints the distribution of those sites at which a given drug acts. When combined with 2-DG autoradiography, the intensity and direction of the action at each of these sites, as well as the impact of these actions on additional sites, can be appreciated. In addition to identification of sites of drug action, brain imaging studies can be used to identify classes of drug action, interactions between drugs, and, perhaps more than any other technique, enhance the appreciation of the similarities and differences between the effects in animals and those in humans. When applied to drugs of abuse, brain imaging studies can be used to help identify key physiological events underlying drug reinforcement as well as those important for various physiological effects of each drug. Armed with such information, brain imaging techniques can play a unique role as one component of an effort to discover pharmacotherapies for drug abuse.

Animals↗

PubMed1994

Pharmacology of a mixed 5-hydroxytryptamine1A/dopamine agonist.

U-67413B (4-hydroxydipropylaminodihydrophenalene) bound with high affinity to both 5-hydroxytryptamine (HT)1A and D2-dopamine (DA) receptor sites. U-67413B depressed 5-HT and DA cell firing rates and depressed synthesis of both neurotransmitters. The drug depressed mouse body temperatures by an amount similar to that for buspirone, gepirone and ipsapirone, but less than that for 8-hydroxy-N,N-dipropyl-2-aminotetralin. In rats, it produced the 5-HT1A behavioral syndrome. In contrast to 5-HT1A agonists having DA antagonist effects, U-67413B mildly depressed rather than stimulated firing rates of noradrenaline (NA) neurons in the locus ceruleus by a non-alpha-2 receptor mechanism. In behavioral tests designed to measure anxiolytic activities, U-67413B was a slightly more effective anxiolytic than standard 5-HT1A anxiolytics (buspirone, gepirone and ipsapirone). The data are consistent with the hypothesis that effects of 5-HT1A agonists on NA neuron activity are mediated through effects on dopaminergic mechanisms, and that effects on NA neurons could modulate anxiolytic activities of 5-HT1A agonists.

Animals↗

PubMed1994

Characterization of U-92016A as a selective, orally active, high intrinsic activity 5-hydroxytryptamine1A agonist.

The purpose of the present study was to characterize U-92016A [(+)-R)-2-cyano-N,N-dipropyl-8-amino-6,7,8,9-tetrahydro-3H-benz[e] indole] as a 5-hydroxytryptamine (5-HT)1A receptor agonist and to compare its activity with that of standard 5-HT1A receptor agonists. U-92016A binds with high affinity to human 5-HT1A receptors expressed in Chinese hamster ovary cells (Ki = 0.2 nM). Radioligand binding studies also indicate that U-92016A is selective for the 5-HT1A receptor over other biogenic amine receptors. In Chinese hamster ovary cells expressing the human 5HT1A receptor, U-92016A decreased the forskolin-induced increase in cyclic AMP synthesis and had an intrinsic activity of 0.82 relative to 5-HT. U-92016A potently decreased rectal temperature in mice. The maximum temperature decrease was significantly greater than that observed for 8-hydroxy-di-n-propyl aminotetralin, buspirone, gepirone, ipsapirone or flesinoxan. U-92016A also elicited the 5-HT-mediated syndrome in rats and resulted in a dose-related decrease in 5-hydroxytryptophan accumulation. The compound also decreased arterial blood pressure in spontaneously hypertensive rats and inhibited sympathetic nerve activity in cats. In these assays U-92016A displayed excellent potency and a long duration of action. U-92016A also inhibited the firing of dorsal raphe 5-HT neurons and was active in two social interaction assays. The p.o. bioavailability of U-92016A was calculated to be 45%. Taken together, these data indicate that U-92016A is a metabolically stable, p.o. active 5-HT1A receptor agonist with an exceptionally high degree of intrinsic activity.

5-Hydroxytryptophan↗

PubMed1994

Excitation of noradrenergic cell firing by 5-hydroxytryptamine1A agonists correlates with dopamine antagonist properties.

The 5-HT1A receptor agonists buspirone, 8-hydroxy-N,N-dipropyl-2-aminotetralin, gepirone and ipsapirone were evaluated for their receptor binding profiles and their effects on firing rates of 5-HT, dopamine (DA) and noradrenaline (NA) neurons in the dorsal raphe, substantia nigra pars compacta and the locus ceruleus, respectively. All agents bound to 5-HT1A receptors with high affinities. All agents also bound to dopamine D2 receptors but, with the exception of buspirone, affinities were usually much lower than for 5-HT1A receptors. All agents depressed 5-HT neurons, with 8-hydroxy-N,N-dipropyl-2-aminotetralin having a potency about 8 to 12 times those for the other three. All agents also antagonized the inhibition of DA neurons by amphetamine, an index of DA antagonist properties. Buspirone reversed amphetamine's effects with doses similar to those for depressing 5-HT neurons, but the remaining three required much higher doses to affect DA neuron function. All four 5-HT1A agonists excited NA neurons. In each case, doses required for excitation of NA cells were similar to those reversing amphetamine's effects on DA cells, but not to those for depressing 5-HT cells. Haloperidol also stimulated NA cells. It is concluded that excitation of NA neurons by 5-HT1A agonists may be due to interactions with dopaminergic, rather than serotonergic, receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1993

Substituted 3-phenylpiperidines: new centrally acting dopamine autoreceptor antagonists.

The (+)-and (-)-enantiomer of compounds 4 and 5 were synthesized and tested for central dopamine (DA) receptor stimulating activity, using biochemical and behavioral tests in rats. Based on the available data the (-)-enantiomers of 4 and 5 are characterized as centrally acting DA autoreceptor antagonists with oral activity. They display a similar pharmacological profile as the prototype DA autoreceptor antagonists (+)-1 and (+)-2 and show a certain preference for the D3 DA receptor antagonist binding site.

Animals↗

PubMed1993

Antagonism of cocaine self-administration by the preferential dopamine autoreceptor antagonist, (+)-AJ 76.

(+)-AJ 76 is a presumed preferential dopamine (DA) autoreceptor antagonist which, in previous behavioral investigations, has displayed properties characteristic of both DA agonists and DA antagonists. In an attempt to test the hypothesis that (+)-AJ 76 might be an effective cocaine pharmacotherapy, the present experiments evaluated (+)-AJ 76's behavioral profile in 3 standard reinforcement paradigms. In the first experiment, (+)-AJ 76 paralleled a DA antagonist in that it failed to support self-administration behavior at all doses (0.1, 0.32, and 1.0 mg/kg/inj) tested. In the second experiment, (+)-AJ 76 (0.9, 3.5, and 14.0 mg/kg) closely resembled the DA agonist D-amphetamine (0.25, 1.0, and 4.0 mg/kg) in producing a clear dose-dependent conditioned place preference. In the third experiment, (+)-AJ 76 (1.88, 3.75, 7.5, 15.0, and 30.0 mg/kg) significantly reduced breaking points (BPs), increased rates of responding, and delayed the onset of responding for cocaine. While (+)-AJ 76 mimics a typical DA antagonist in its ability to reduce BPs and augment rates of responding for cocaine, recent evidence suggests that it more closely resembles a DA agonist in its ability to delay the onset of responding for cocaine. In summary, the present investigations have shown that (+)-AJ 76's profile in 3 reinforcement paradigms is unusual and not exclusively representative of either DA agonists or DA antagonists. The potential utility for such an agent in treating cocaine abuse is discussed.

Animals↗

PubMed1993

Novel 2-substituted tetrahydro-3H-benz[e]indolamines: highly potent and selective agonists acting at the 5-HT1A receptor as possible anxiolytics and antidepressants.

The synthesis of (+)-(R)-2-cyano-N,N-dipropyl-8-amino-6,7,8,9-tetrahydro-3H- benz[e]indole [(R)-14, U92016A], a potent 5-HT1A agonist, and related analogs is described. In vitro binding studies show that the (R)-enantiomers of this series possess the highest potency for the 5-HT1A receptor. In vivo hypothermia correlates with this, with the (R)-enantiomers causing a greater temperature drop than the (S)-enantiomers. The most active compound in 5-HT1A binding and in the in vivo models was (R)-14, which was found to be highly potent as an agonist in single cell firing studies, as well as potent and of very high intrinsic activity in mouse hypothermia and the sympathetic nerve discharge (SND) models. An in vivo duration of action study, following SND, showed (R)-14 to possess a long duration of action. The synthesis via a nitrene insertion, determination of absolute configuration, and biological activities of this series is described.

Animals↗

PubMed1993

Synthesis and biological activity of cis-(3aR)-(-)-2,3,3a,4,5,9b-hexahydro- 3-propyl-1H-benz[e]indole-9-carboxamide: a potent and selective 5-HT1A receptor agonist with good oral availability.

The synthesis and biological activity of cis-(3aR)-(-)-2,3,3a,4,5,9b- hexahydro-3-propyl-1H-benz[e]indole-9-carboxamide ((-)-3a), U93385, is described. The cis racemate and its enantiomer as well as the corresponding trans enantiomers were also synthesized and evaluated. The synthesis of these analogs was achieved via either a four-step conversion of the 9-hydroxy precursor into 9-carboxamide or an alternative synthesis using the (R)-alpha-methylbenzyl group as the chiral auxiliary. The cis racemate (+/-)-3a, was found to be a selective and potent 5-HT1A receptor agonist with the activity residing in the cis-(3aR)-enantiomer, (-)-3a. The cis-(3aS)-enantiomer (+)-3a and trans-(3aR)-enantiomer (-)-3b displayed partial 5-HT1A agonist activity whereas the other trans-(3aS)-enantiomer (+)-3b showed no activity. The enantiomer (-)-3a was found to be selective in both in vitro and in vivo biochemical/behavioral assays. This compound potently reduced rectal temperature in mice, decreased the firing rate of rat midbrain serotonergic neurons, and suppressed rat brain 5-HT synthesis. This compound also reduced sympathetic nerve discharge and blood pressure in the anesthetized cat and showed activity in the forced swim assay in mice. It exhibited good oral activity in behavioral and biochemical assays and, in fact, had a 46% oral availability in the rat when comparing blood levels of parent drug after iv and po administration. This compound has demonstrated a potential for anxiolytic and antidepressant activity and is currently undergoing clinical evaluation.

Administration, Oral↗

PubMed1993

Centrally acting serotonergic and dopaminergic agents. 1. Synthesis and structure-activity relationships of 2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole derivatives.

The synthesis and structure-activity relationships (SAR) of 2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole derivatives (3) are described. These compounds are conformationally restricted, angular tricyclic analogs of 2-aminotetralin. The synthesis was achieved in several steps from the corresponding 2-tetralones. The enantiomers of the cis analogs were obtained from either fractional recrystallizations of the diastereomeric salts of di-p-toluoyl-L-(or D)-tartaric acid or an asymmetric synthesis using chiral (R)-alpha-methylbenzylamine. All analogs were evaluated in the in vitro 5-HT1A and D2 binding assays and selected analogs were investigated further in biochemical and behavioral tests. Analogs with 9-methoxy substitution (R1 in 3) showed mixed 5-HT1A agonist and dopamine antagonist activities whereas the corresponding 9-hydroxy analogs displayed selective 5-HT1A agonist activity. The cis analogs were found to be more potent than the corresponding trans analogs and in the cis series, the (3aR)-(-)-enantiomers displayed higher potency. Nitrogen substitution (R2 in 3) with either an n-propyl or an allyl group produced similar activities whereas replacement with a bulky alpha-methylbenzyl group resulted in loss of activity. Analogs without aromatic substitution (R1 = H in 3) still showed good 5-HT1A agonist activity, although less potent than the 9-methoxy series. In this case, the trans analogs possessed equal or higher in vitro 5-HT1A affinity than the corresponding cis analogs. Analogs with either 6-methoxy or 6-hydroxy substitution (R1 in 3) were found to display dopamine antagonist properties. However, only N-allyl analogs showed this activity. In the 6-methoxy-N-allyl series, the cis analog was found to be more potent than the trans analog. Again, between the pair of cis enantiomers, the (3aR)-(-)-enantiomer showed higher potency. Incorporation of an additional methyl group into 9-methoxy cis analogs at C-2 resulted in retention of potent 5-HT1A agonist activity.

Animals↗

PubMed1993

Centrally acting serotonergic and dopaminergic agents. 2. Synthesis and structure-activity relationships of 2,3,3a,4,9,9a-hexahydro-1H-benz[f]indole derivatives.

The conformationally restricted linear tricyclic analogs of 5- and 8-hydroxy-2-(di-n-propylamino)-tetralins were investigated for their serotonergic and dopaminergic properties. These cis and trans analogs of 2,3,3a,4,9,9a-hexahydro-1H-benz[f]indole (3), where a five-membered ring is fused between the nitrogen and C-3 carbon of 2-aminotetralin, were synthesized from 5-methoxy- and 8-methoxytetralones. The enantiomers of trans-5-methoxy-N-n-propyl and -N-allyl analogs were obtained via fractional recrystallization of their di-p-toluoyl-L (or D) tartaric acid salts. All analogs were evaluated in the in vitro 5-HT1A and D2 binding assays and selected analogs were investigated further in biochemical and behavioral tests. In the 5-substituted series (R1 in 3), the trans isomers were found to possess higher levels of pharmacological activity then the corresponding cis isomers. The trans-5-methoxy analogs showed selective 5-HT1A receptor activity in vitro but displayed mixed 5-HT1A and D2 agonist properties in vivo. The corresponding trans-5-hydroxy analogs were found to be potent D2 agonists with full intrinsic activity. An examination of nitrogen substitution (R2 in 3) revealed that analogs with either an allyl or an n-propyl group displayed equipotent activities. Substitution with a cyclopropylmethyl or benzyl group resulted in reduced activity. Among the resolved analogs tested, the activity was found to reside exclusively in the (3aS)-(-)-enantiomers. In the 8-substituted series (R1 in 3), only 8-methoxy-N-allyl analogs were synthesized and evaluated. In this case, both cis and trans isomers showed equally weak in vitro 5-HT1A receptor agonist activity devoid of dopaminergic effects. The presence of an additional methyl group at the C-2 position (R3 in 3) of the cis-(+/-)-8-methoxy-N-n-propyl analog resulted in enhancement of in vitro 5-HT1A receptor binding affinity, with the (2 beta,3a alpha,9a alpha)-(+/-)-isomer displaying potency 35 times greater than the (2 alpha,3a alpha,9a alpha)-(+/-)-isomer.

Animals↗

PubMed1993

Centrally acting serotonergic agents. Synthesis and structure-activity relationships of C-1- or C-3-substituted derivatives of 8-hydroxy-2-(di-n-propylamino)tetralin.

The synthesis and structure-activity relationships (SAR) of C-1- or C-3-substituted derivatives of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) are described. These analogs were synthesized via alkylation of the tetralone derivatives followed by reductive amination. All of the analogs were inactive at the dopamine D2 receptor. Among the 8-OMe or 8-OH C-1,N-disubstituted analogs synthesized, the cis analogs were more potent in the 5-HT1A binding assay than the corresponding trans analogs. However, in the case of 1-(cyclopropylmethyl)-N-n-propyl analogs, the trans isomer has a slightly higher 5-HT1A affinity than its cis counterpart. The order of binding potency for C-1 substitution was found to be allyl > hydroxymethyl > n-propyl > cyclopropylmethyl >> carbomethoxy. Interestingly, the 5-OMe analogs were found to be inactive in both the 5-HT1A and dopamine D2 binding assays. In the C-3 allyl-substituted analogs, 5-HT1A agonist activity was found to be considerably lower. In these examples, the trans analogs showed weak 5-HT1A binding activity whereas the cis analogs were inactive. Analogs with C-1,N,N-trisubstitution also showed a marked decrease in 5-HT1A binding affinity. Overall, the SAR study showed that cis C-1 substitution maintains the 5-HT1A agonist activity of 8-OH-DPAT whereas trans C-1 substitution displays somewhat diminished activity. On the other hand, the trans C-3 substitution shows modest agonist activity whereas cis C-3 substitution removes the activity completely.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1993

Evaluation of the reinforcing and discriminative stimulus effects of cocaine in combination with (+)-AJ76 or clozapine.

Because self-administration and discrimination of a drug by animals correlate with its abuse and subjective effects in humans, interventions that modify the reinforcing and discriminative stimulus effects of the drug may be useful in the treatment of its abuse. The present study was designed to evaluate the effects of the putative dopamine autoreceptor antagonist (+)-AJ76 (AJ) or the atypical antipsychotic clozapine (CLZ) on the reinforcing and discriminative stimulus effects of cocaine in monkeys. One group of rhesus monkeys (n = 6) was allowed to self-administer cocaine (0.03 or 0.1 mg/kg/injection i.v. fixed-ratio 10, 2 hr/day). A second group of monkeys (n = 5) was trained to discriminate cocaine (0.2 or 0.4 mg/kg i.m., 10 min presession) from saline in a two lever, food-reinforced, drug discrimination paradigm. When behavior was stable, AJ or CLZ was administered i.m., 15 or 30 min presession. Intermediate doses of both compounds (1.0-3.0 mg/kg of AJ; 0.3-1.0 mg/kg of CLZ) increased cocaine self-administration, while responding remained evenly distributed over the session. A higher dose of CLZ decreased cocaine self-administration in an apparently nonspecific manner. When combined with saline, partial substitution for cocaine was seen in one of three monkeys with AJ and in none with CLZ. In combination with the training dose of cocaine in the discrimination experiment, both AJ and CLZ decreased drug appropriate responding by at least 50% in two of four monkeys, but had little or no effect in the other monkeys up to doses that completely suppressed lever pressing (6.4 mg/kg of AJ; 3.2 mg/kg of CLZ). Taken together, the present findings suggest that any blockade of the reinforcing and discriminative stimulus effects of cocaine by AJ and CLZ was, at best, partial. Furthermore, the stimulant effects of AJ observed in rats were not prominent in monkeys.

Animals↗

PubMed1992

Antagonism of cocaine's pharmacological effects by the stimulant dopaminergic antagonists, (+)-AJ76 and (+)-UH232.

The aminotetralins (+)-AJ76 and (+)-UH232 are stimulant dopaminergic antagonists, which may preferentially antagonize autoreceptors of dopamine nerve terminals. Both agents antagonized cocaine's depressant effects on firing rates of ventral tegmental dopaminergic neurons, but (+)-UH232 was much more potent. When injected simultaneously with cocaine, (+)-UH232 inhibited and (+)-AJ76 enhanced the locomotor stimulation observed during the first 30 min following s.c. cocaine administration. However, (+)-AJ76 antagonized cocaine-induced stereotypies as well as the later more intense cocaine locomotor stimulation. It is suggested that preferential dopamine autoreceptor antagonists may provide a novel approach to a pharmacotherapy for treating cocaine abuse.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

Novel indolodioxanes with antihypertensive effects: potent ligands for the 5-HT1A receptor.

The synthesis and biological evaluation of a new family of tricyclic indolodioxanes is described. These compounds all contain the 2,3-dihydro-7H-1,4-dioxino[2,3-e]indole nucleus and bear substituents at the 2 and/or 8 positions. Thirteen members of this class were prepared and shown to be potent ligands for the 5-HT1A receptor, with several compounds displaying subnanomolar inhibition constants. These compounds also bind to the dopamine D-2 receptor, but generally with higher inhibition constants than those for 5-HT1A. Certain members of this novel structural class show in vivo activity in the mouse hypothermia assay. One of these compounds, U-86192A, has been shown to have antihypertensive effects in the cat, completely eliminating sympathetic nerve discharge at 1 mg/kg iv and lowering mean arterial pressure to 50% pretreatment levels. These effects can be reversed by the administration of spiperone, indicating that U-86192A is acting via a central serotonergic mechanism.

Animals↗

PubMed1992

Dopaminergic and serotonergic activities of imidazoquinolinones and related compounds.

The synthesis of 5-(dipropylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij] quinolin-2(1H)-one (5), a potent dopamine D2 agonist showing high dopamine/serotonin (5HT1A) selectivity, is described. Dopaminergic activity is associated with the (R)-enantiomer of 5; the (S)-enantiomer shows no dopaminergic activity. A series of analogues where the imidazolone ring was modified to various 5- or 6-membered heterocyclic rings were prepared. Some of these compounds showed a combination of dopaminergic and serotonergic activity, while one compound, 6-(dipropylamino)-1,2,6,7-tetrahydro-3H,5H-pyrido[3,2,1- ij]quinazolin-3-one (24), was a selective serotonergic agonist. Various analogues of 5 where the dipropylamine substituent was modified were prepared. Most of these showed reduced dopaminergic activity, while several were as potent as 5 at the serotonin 5HT1A receptor. Orientations for the new compounds at dopamine and serotonin receptors are proposed and compared with those of other tricyclic ligands known to have high affinity at these receptors.

Aminoquinolines↗

PubMed1992

Effects of the putative dopamine autoreceptor antagonists (+)-AJ 76 and (+)-UH 232 on the discriminative stimulus properties of cocaine.

Recent evidence suggests that the putative dopamine (DA) autoreceptor antagonists, (+)-AJ 76 and (+)-UH 232, share some neurochemical and behavioral effects with both psychostimulants and neuroleptics. The ability of (+)-AJ 76 and (+)-UH 232 to mimic or antagonize the stimulus effects of cocaine was investigated in rats trained to discriminate 5 mg/kg (N = 8) or 10 mg/kg (N = 8) of cocaine from saline in a two-lever, water-reinforced, drug discrimination task. In the cocaine (10 mg/kg) group, administration of (+)-AJ 76 (2.5-20 mg/kg) engendered only a partial substitution for cocaine (maximum 60% cocaine-lever responses). Given in combination with cocaine (10 mg/kg), (+)-AJ 76 (2.5-40 mg/kg) did not significantly attenuate the cocaine cue. A fixed dose of (+)-AJ 76 (2.5 or 10 mg/kg) plus various doses of cocaine (1.25-5 mg/kg) did not alter the cocaine dose-response curve. (+)-UH 232 (2-16 mg/kg) produced primarily saline-appropriate responding in rats trained to discriminate 5 mg/kg of cocaine and was unable to block the interoceptive cocaine state when given in combination with cocaine (5 mg/kg). (+)-UH 232 (2 or 8 mg/kg) also did not alter the cocaine dose-response curve. These results suggest that (+)-AJ 76 and (+)-UH 232 elicit only weak or no cocaine-like stimulus effects and, unlike neuroleptics, do not attenuate the cocaine cue.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1992

Effect of the anticonvulsant U-54494A on cortical neuron excitability: comparison to the kappa agonist U-50488H.

U-54494A, a 1,2-diamine anticonvulsant, and U-50488H, a structurally related agonist for opiate kappa receptors, were tested for effects on spontaneous and glutamate-evoked firing rates in cerebral cortex of urethane-anesthetized male Sprague-Dawley rats. Iontophoretic application of 1,2-diamines, glutamate diethyl ether (GDEE), or procaine depressed spontaneous and amino acid-induced firing of cortical neurones. With continued ejection of 1,2-diamines or procaine, firing was silenced completely, but GDEE could maintain a partial suppression. A rapid rebound of excitation followed cessation of procaine ejections, but not of other agents. Procaine, but not U-54494A, blocked axonal conduction of rabbit sciatic nerve. Intravenous U-54494A and U-50488H significantly depressed spontaneous firing rates of cortical neurones, but only the U-50488H effects were antagonized by naloxone. It is concluded that U-54494A inhibits neuronal excitability by a mechanism independent of the analgesic kappa receptor. Biochemical and physiological studies have demonstrated that U-54494A and the kappa opioid agonist U-50488H (a structurally related diamine) (1) have anticonvulsant activity (2, 3). U-54494A lacks kappa analgesic and sedative properties, and it has been suggested that the mechanism of action of this compound may be mediated by a subtype of kappa opioid receptor (3). The effects of kappa analgesics on neuronal firing in nociceptive pathways have been described (4, 5). However, no previous electrophysiological studies on U-54494A have been done. Since U-54494A antagonizes amino acid-induced seizures (3), the interactions of this compound with glutamate are of interest. In the present study, the antagonist efficacies of U-54494A and U-50488H for inhibiting spontaneous and 1-glutamate stimulated neurons of the rat prefrontal cerebral cortex were assessed after i.v. and microiontophoretic administration of the compounds. Effects observed with these routes of administration allow the observation of neuronal changes occurring immediately after administration and take advantage of the high temporal resolution provided by the electrophysiological recording techniques of single cells. A preliminary account of portions of this work have been previously disclosed (6).

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗