Comparison of the potency of MDL 100,907 and SB 242084 in blocking the serotonin (5-HT)(2) receptor agonist-induced increases in rat serum corticosterone concentrations: evidence for 5-HT(2A) receptor mediation of the HPA axis.

Direct-acting serotonin (5-HT) receptor agonists increase serum corticosterone in rats by activating receptors of the 5-HT(1A) or the 5-HT(2A/2C) subtypes. While involvement of 5-HT(1A) receptors in activation of the hypothalamic-pituitary-adrenocortical (HPA) axis is clear, the 5-HT(2) receptor subtype--5-HT(2A) or 5-HT(2C)--responsible for activation of the HPA axis by direct-acting 5-HT(2) receptor agonists has been difficult to determine due to the lack of selective pharmacologic agents. Recently, however, 5-HT(2) receptor antagonists with high selectivity for 5-HT(2A) and 5-HT(2C) receptor subtypes have been discovered. The selective 5-HT(2A) receptor antagonist MDL 100,907 and the selective 5-HT(2C) receptor antagonist SB 242084 were used to block the increases in rat serum corticosterone elicited by 5-HT(2) receptor agonists with varying degrees of affinity for 5-HT(2A) and 5-HT(2C) receptors. MDL 100,907 was fully effective in blocking the increases in corticosterone concentrations produced by quipazine, DOI, m-CPP and Ro 60-0175, whereas SB 242084 was ineffective or was only marginally effective. Our findings implicate 5-HT(2A) receptors rather than 5-HT(2C) receptors in mediating increases in rat serum corticosterone produced by direct-acting 5-HT(2) receptor agonists in vivo.     

Prior chronic exposure to cocaine inhibits the serotonergic stimulation of ACTH and secretion of corticosterone.

The effect of long-term pretreatment with cocaine on serotonergic regulation of ACTH (adrenocorticotropic hormone; corticotropin) and secretion of corticosterone in rats was investigated. The following observations were made: (1) Pretreatment with cocaine had no significant effect on basal levels of ACTH and corticosterone in plasma. However, cocaine caused a reduction in the ability of the 5-HT (5-hydroxytryptamine, serotonin) releaser p-chloroamphetamine (PCA) to increase corticosterone in plasma, 42 hr after the last injection of cocaine. (2) Exposure to cocaine for 7 days was sufficient to produce a maximal inhibition of the PCA-induced increase in ACTH in plasma. (3) The inhibitory effect of cocaine on PCA-induced release of ACTH was more marked than on corticosterone. (4) Conversely, the dose-dependent stimulatory effect of two 5-HT1 agonists, RU 24969 (5-methoxy-3-(1,2,3,4-tetrahydro-4-pyridinyl)-1H-indole) and m-CPP (m-chlorophenylpiperazine), on ACTH and corticosterone was not reduced by 7 days of exposure to cocaine. Taken together, these findings indicate that pretreatment with cocaine reduced the function of serotonergic nerve-terminals but not postsynaptic receptors, that stimulate ACTH and secretion of corticosterone.     

Effect of serotonin (5-HT)1B receptor ligands on cocaine sensitization in rats

Recent studies have shown that antagonists of serotonin (5-HT)1B receptors attenuate cocaine-induced locomotor hyperactivity, whereas agonists enhance reinforcing and discriminative stimulus effects of the psychostimulant. The present study was designed to determine how 5-HT1B receptor ligands affected the development or the expression phase of sensitization to the cocaine-induced locomotor response in rats. In Experiment 1, rats were treated repeatedly (for 5 days) with cocaine (10 mg/kg) in combination with either saline, GR 127935 (5-HT1B antagonist), CP 94,253 (5-HT1B agonist) or GR 127935 + CP 94,253. On day 10, they received a challenge dose of cocaine (10 mg/kg). In Experiment 2, animals received either saline or cocaine (10 mg/kg) for 5 days, and were then challenged with cocaine (10 mg/kg) in combination with saline, GR 127935, CP 94,253 or GR 127935 + CP 94,253, on day 10. In Experiment 3, rats received either saline, cocaine or CP 94,253 for 5 days; on day 10 they received challenge doses of CP 94,253 or cocaine. In rats treated repeatedly with cocaine, the locomotor hyperactivity induced by a challenge dose of the psychostimulant was about twice as high as that observed after its first administration. The effect evoked by cocaine challenge was further increased in animals treated repeatedly with CP 94,253 + cocaine, but not with GR 127935 + CP 94,253 + cocaine. No difference was observed in the response to cocaine challenge in rats treated repeatedly with cocaine or GR 127935 + cocaine (Experiment 1). In animals treated repeatedly with the psychostimulant, the behavioral response to a challenge dose of cocaine was dose-dependently increased when that drug was combined with CP 94,253, but not with GR 127935 + CP 94,253. No difference was observed in the locomotor response of rats challenged with cocaine or GR 127935 + cocaine (Experiment 2). When rats were treated repeatedly with cocaine, a challenge dose of CP 94,253 produced an about threefold increase in the locomotor effect compared to the animals treated likewise with saline (Experiment 3). Our results indicate that 5-HT1B receptors are involved in neither the development nor the expression of sensitization to cocaine-induced locomotor hyperactivity. On the other hand, they also show that pharmacological activation of 5-HT1B receptors enhances both phases of this phenomenon, and that repeated administration of cocaine leads to an increased functional reactivity of these receptors.     

Contribution of serotonin (5-HT) 5-HT2 receptor subtypes to the discriminative stimulus effects of cocaine in rats

Rationale The serotonin (5-hydroxytryptamine; 5-HT) 5-HT₂ receptor (5-HT₂R) family is an important regulator of the behavioral responsiveness to cocaine. Objective The present study is an analysis of the role of the 5-HT₂R subtypes (5-HT_2AR, 5-HT_2BR, and 5-HT_2CR) in the discriminative stimulus effects of cocaine. Methods Male Wistar rats were trained to discriminate cocaine (10 mg/kg) from saline in a two-lever, water-reinforced FR 20 task, and we investigated the ability of the 5-HT_2AR antagonist 1(Z)-[2-(dimethylamino)ethoxyimino]-1(2-fluorophenyl)-3-(4-hydroxyphenyl)-2(E)-propene (SR 46349B), the 5-HT_2BR antagonist N-(1-methyl-5-indolyl)-N′-(3-methyl-5-isothiazolyl) urea (SB 204741), and the 5-HT_2CR antagonist [(+)-cis -4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo(1,7-bC)(2,6)naphthyridine (SDZ SER-082) to substitute for or to modulate the stimulus effects of cocaine. Results Pretreatment with SR 46349B (0.5–1 mg/kg) resulted in a rightward shift of the cocaine dose–response curve, while SDZ SER-082 (1 mg/kg) shifted the dose–response for cocaine to the left; SB 204741 (1–3 mg/kg) was inactive. Conclusions Our pharmacological analyses of selective antagonists of 5-HT_2AR, 5-HT_2BR, and 5-HT_2CR indicate oppositional influence of 5-HT_2AR and 5-HT_2CR on the stimulus effects of cocaine and exclude a role for the 5-HT_2BR. These data suggest that 5-HT_2AR and 5-HT_2CR may be important in modulating the subjective effects of cocaine in humans.     

Drug-induced penile erections in rats: indications of serotonin1B receptor mediation

The induction of penile erections by a variety of compounds with a direct or indirect effect on serotonin (5HT) receptors was investigated in rats. L-5-Hydroxy-tryptophan (L-5HTP) induced penile erections when co-administered with nialamide and the peripheral decarboxylase inhibitor benserazide, indicating that the site of action for inducing penile erections is within the central nervous system. Penile erections were also induced by the 5HT uptake inhibitors zimelidine, fluoxetine, citalopram, Org 6997, by the 5HT-releasing agent fenfluramine and by the putative 5-HT1B receptor agonist 1-(3'-chlorophenyl)-piperazine (mCPP). The 5HT1A-agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) did not induce penile erections. The less selective 5HT receptor agonists 5-methoxy-N,N-dimethyl-tryptamine (5MeODMT), 5-methoxytryptamine (5MeOT), dl-lysergic acid diethylamide (LSD) and Ru 24969 were also ineffective. Induction of penile erections by quipazine appeared only when this compound was co-administered with the 5HT2 receptor antagonist pirenperone. Receptor antagonists were tested against penile erections induced by Org 6997. The beta-adrenoceptor antagonists that also have 5HT1 antagonistic properties, (S)-pindolol and dl-propranolol, antagonized Org 6997-induced penile erections but butoxamine and metoprolol did not. Spiperone and pirenperone in doses selective for 5HT1A and 5HT2 receptors respectively were also inactive. Haloperidol, 0.46 mg/kg, partially attenuated penile erections induction. The data are discussed in the light of the hypothesis that penile erections induction by serotonin-mimetic compounds is mediated by 5HT1B receptors in the striatum.     

Ketanserin attenuates the behavioural effects of corticosterone: implications for 5-HT(2A) receptor regulation.

The effects of chronic corticosterone treatment on sexual behaviour and wet-dog shakes were investigated in both female and male rats. The serotonergic type 2A (5-HT(2A)) receptor antagonist ketanserin was administered to test the hypothesis that the behavioural effects of corticosterone were mediated by increased 5-HT(2A) receptor activity. Rats were randomly assigned to one of four chronic treatment groups: control, ketanserin alone, corticosterone alone, or ketanserin and corticosterone. Ketanserin attenuated the corticosterone-induced changes in both sexual behaviour and wet-dog shakes. Ketanserin alone had no effect on these behaviours. Results suggest that increased 5-HT(2A) receptor activity mediates the effects of corticosterone on sexual behaviour and wet-dog shakes.     

Previous exposure to cocaine enhances cocaine self-administration in an alpha 1-adrenergic receptor dependent manner.

Noradrenergic transmission is implicated in the biochemical and behavioral effects of cocaine. Recently, we demonstrated that the alpha 1-adrenergic receptor antagonist prazosin attenuates cocaine-induced reinstatement of drug-seeking behavior. We now assessed whether prazosin could counter the effect of previous exposure to cocaine to enhance subsequent self-administration behavior. Rats were pre-exposed to systemic injections of either saline, prazosin (0.3 mg/kg), saline+cocaine (10 mg/kg), or prazosin+cocaine for 5 days. Starting 15-18 days after the last pre-exposure injection, rats were trained to self-administer cocaine (0.5 mg/kg/infusion) under a fixed ratio 3 (FR3) schedule of reinforcement. Several tests were conducted. First, responding for cocaine under an FR3 schedule was assessed across several doses (0.125-1.0 mg/kg/infusion). Second, responding for cocaine (0.5 mg/kg/infusion) under a progressive-ratio (PR) schedule was examined for 6 consecutive days. Finally, responding for cocaine (0, 0.5, and 1.0 mg/kg/infusion) was determined under the PR schedule of reinforcement. Results showed that cocaine pre-exposed rats self-administer more cocaine compared to saline pre-exposed rats when tested under both the FR and PR schedules. Rats pre-exposed to cocaine plus prazosin did not show enhanced cocaine self-administration. These rats, as well those pre-exposed to prazosin alone, showed levels of cocaine self-administration similar to saline pre-exposed rats. Thus, previous exposure to cocaine enhanced cocaine self-administration, an effect that appears to involve activation of alpha 1-adrenergic receptors. These data, along with several recent studies, show further support for the contribution of noradrenergic transmission in the behavioral effects of cocaine.     

Effects of serotonin (5-HT)6 receptor ligands on responding for cocaine reward and seeking in rats

The endogenous brain serotonin (5-HT) system is believed to have an important modulatory influence in mediating drug reward and seeking mechanisms. Data from preclinical behavioral studies have provided emerging evidence that 5-HT(6) receptors, among other 5-HT receptors, may play a significant role in the mechanisms of action of psychostimulant addicted drugs. The aim of the present study was to investigate whether the selective pharmacological blockade or activation of 5-HT(6) receptors altered the maintenance of cocaine self-administration, reinstatement of cocaine-seeking behavior following an extinction of cocaine self-administration or cocaine-evoked conditioned place preference in rats. We also evaluated the effects of 5-chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-3-methyl)-2-benzothiophene-sulfonamide (SB 271046, a 5-HT(6) receptor antagonist) or N-1-(6-chloroimidazo-[2,1-b]-[1,3]thiazole-5-sulfonyl)tryptamine (WAY 181187, a potent 5-HT(6) receptor agonist) on locomotor activity in rats. Our results indicate that SB 271046 (1-10 mg/kg) altered cocaine-maintained self-administration as well as cocaine-evoked reinstatement of cocaine seeking and expression of cocaine place preference in rats.We also demonstrate that pharmacological stimulation of 5-HT(6) receptors by WAY 181187 (3-30 mg/kg) attenuated the expression of cocaine conditioned place preference but not cocaine self-administration and reinstatement of cocaine seeking. WAY 181187 at the highest dose used (30 mg/kg) reduced basal locomotor activity. Despite current results, the precise function and therapeutic relevance of 5-HT(6) receptors need further clarification.     

Selective agents for serotonin2C (5-HT2C) receptor

The serotonin2C (5-HT2C) receptor has attracted a lot of attention owing to its role in appetite regulation, depression, obsessive-compulsive disorder (OCD), panic disorders, and substance abuse. This review summarizes non-patent and patent literature up to November 2005 that deals with the synthesis and characterization of selective 5-HT2C receptor agonists and antagonists. Highlights on structure-activity relationships have been included, when possible.     

Role of serotonin (5-HT)2 receptors in cocaine self-administration and seeking behavior in rats

Previous studies have indicated a role of serotonin (5-HT)2 receptors in modulation of the behavioral effects of cocaine. In the present study, the efficacy of SR 46349B (a 5-HT(2A) receptor antagonist) or SDZ SER-082 (a 5-HT(2C) receptor antagonist) in altering cocaine seeking behavior was examined in rats. Rats were trained to press a lever for cocaine (0.5 mg/kg/infusion, iv) paired with the cue (light + tone). After stabilization of self-administration response, the animals underwent daily extinction sessions during which responding had no consequences. The cocaine seeking behavior was reinstated by cocaine priming (10 mg/kg, ip) or by presentation of the cue. Neither SR 46349B (0.25-1 mg/kg) nor SDZ SER-082 (0.25-1 mg/kg) altered the maintenance of cocaine self-administration. SR 46349B (0.5-1 mg/kg) decreased responding to the cocaine priming dose and reduced cue-induced reinstatement, while SDZ SER-082 failed to alter both cue- and cocaine priming-induced reinstatement. These findings indicate that 5-HT(2A) and 5-HT(2C) receptors are not significant to cocaine rewarding effects. However, they show the importance of the 5-HT(2A) receptors (but not 5-HT(2C) receptors) in cocaine-priming- and cue-provoked reinstatement. Since drugs that reduce cocaine seeking also alleviate cocaine craving, 5-HT(2A) receptor antagonists may be considered to be of possible clinical application for the treatment of cocaine dependence.     

2 beta-substituted analogues of cocaine. Synthesis and inhibition of binding to the cocaine receptor.

The potencies of a series of 2 beta-substituted cocaine analogues to displace [3H]-3 beta-(p-fluorophenyl)tropane-2 beta-carboxylic acid methyl ester binding in rat striatal membranes demonstrate the requirement for a 2 beta-substituent with two hydrogen-bond acceptors. The insensitivity of the ester moiety to steric and electronic factors suggests its modification to provide site-specific irreversible ligands.     

Novel serotonin receptor 2 (5-HT2R) agonists and antagonists: a patent review (2004-2014)

Introduction: Serotonin or 5-hydroxytryptamine (5-HT) is a substance found in plasma, which increases smooth muscle contraction and mediates platelet aggregation. In addition, it is a monoamine neurotransmitter and is implicated in diverse behaviors. The serotonin receptor 2 (5-HT₂) subfamily is best known for biased signaling and is strongly expressed mainly in the brain regions postulated to be involved in the modulation of higher cognitive and affective functions. Modulators of the 5-HT₂ receptor are currently used to treat a variety of diseases including chronic pain and psychonosema. These properties suggest that 5-HT₂ receptors may become an important therapeutic target for the treatment of various pathological conditions.

Areas covered: This review highlights the significant progress that has been made in the discovery and development of 5-HT₂ receptor agonists and antagonists based on an analysis of the patent literature between January 2004 and December 2014.

Expert opinion: Cumulative evidence over the past decade supports the notion that the modulation of 5-HT₂ receptors has a positive effect on human cognition and emotion. Therefore, we suggest that new agonists and antagonists may play an important role in the treatment of disorders such as schizophrenia, addiction and obesity.     

N-Arylsulfonylindole derivatives as serotonin 5-HT(6) receptor ligands.

A series of N(1)-arylsulfonyltryptamines were found to be potent ligands of the human serotonin 5-HT(6) receptor with the 5-methoxy-1-benzenesulfonyl analogue (19) having the highest affinity. Additionally, it was discovered that a group such as 3-(3-methoxybenzyl)-1,2,4-oxadiazol-5-yl in the 2-position of the indole ring (43) can replace the arylsulfonyl substituent in the 1-position with no loss of affinity. This suggested that the binding conformation of the aminoethyl side chain at this receptor was toward the 4-position of the indole ring and was supported by the fact that the 4-(aminoethyl)indoles (45) also displayed high affinity, as did the conformationally rigid 1,3,4,5-tetrahydrobenz[c,d]indole (49). Molecular modeling showed that 19, 43, and 45 all had low-energy conformers that overlaid well onto 49. Both 19 and 49 had good selectivity over other serotonin receptors tested, with 49 also showing excellent selectivity over all dopamine receptors. In a functional adenylate cyclase stimulation assay, 19 and 49 had no agonist activity, whereas 45 behaved as a partial agonist. Finally, it was shown that 19 had good activity in the 5-HT(2A) centrally mediated mescaline-induced head twitch assay, which implies that it is brain-penetrant.     

Selective serotonin 5-HT(2C) receptor activation suppresses the reinforcing efficacy of cocaine and sucrose but differentially affects the incentive-salience value of cocaine- vs. sucrose-associated cues

Serotonin (5-HT) controls affective and motivational aspects of palatable food and drug reward and the 5-HT_2C receptor (5-HT_2CR) has emerged as a key regulator in this regard. We have evaluated the efficacy of a selective 5-HT_2CR agonist, WAY 163909, in cocaine and sucrose self-administration and reinstatement assays employing parallel experimental designs in free-fed rats. WAY 163909 dose-dependently reduced the reinforcing efficacy of cocaine (ID₅₀ = 1.19 mg/kg) and sucrose (ID₅₀ = 0.7 mg/kg) as well as reinstatement (ID₅₀ = 0.5 mg/kg) elicited by exposure to cocaine-associated contextual cues, but not sucrose-associated contextual cues. The ID₅₀ of WAY 163909 predicted to decrease the reinforcing efficacy of cocaine or sucrose as well as reinstatement upon exposure to cocaine-associated cues was ∼5-12-fold lower than that predicted to suppress horizontal ambulation (ID₅₀ = 5.89 mg/kg) and ∼2-5-fold lower than that predicted to suppress vertical activity (ID₅₀ = 2.3 mg/kg). Thus, selective stimulation of the 5-HT_2CR decreases the reinforcing efficacy of cocaine and sucrose in freely-fed rats, but differentially alters the incentive-salience value of cocaine- vs. sucrose-associated cues at doses that do not impair locomotor activity. Future research is needed to tease apart the precise contribution of 5-HT_2CR neurocircuitry in reward and motivation and the learning and memory processes that carry the encoding for associations between environmental cues and consumption of rewarding stimuli. A more complete preclinical evaluation of these questions will ultimately allow educated proof-of-concept trials to test the efficacy of selective 5-HT_2CR agonists as adjunctive therapy in chronic health maladies including obesity, eating disorders and drug addiction.This article is part of a Special Issue entitled ‘Serotonin’.     

Naltrexone, serotonin receptor subtype antagonists, and glucoprivic intake: 2. Insulin.

Opiate antagonist inhibition of deprivation-induced intake and 2-deoxy-D-glucose (2DG) hyperphagia is significantly enhanced by the 5-hydroxytryptamine3 (5-HT3) antagonist, ICS-205,930. Interactions between opiate antagonists and either 5-HT or 5-HT2 antagonists produced smaller effects. The present study evaluated whether insulin (5 U/kg) hyperphagia was affected by methysergide (0.5-5 mg/kg), ritanserin (0.25-2.5 mg/kg), and ICS-205,930 (0.5-5 mg/kg) alone or in combination with naltrexone (2.5-10 mg/kg). Whereas ICS-205,930 stimulated insulin hyperphagia across the 6-h time course, ritanserin and, to a lesser degree, methysergide reduced insulin hyperphagia. Naltrexone marginally (19-33%) reduced insulin hyperphagia. Pairing naltrexone with either ICS-205,930 or ritanserin significantly suppressed insulin hyperphagia after 2 h. Pairing naltrexone with each of the serotonin antagonists significantly enhanced insulin hyperphagia after 4 and 6 h. These data suggest that 5-HT2 and 5-HT3 receptor subtypes interact with opioid systems to modulate insulin hyperphagia. Given that central insulin reduces food intake and body weight, the interaction between serotonergic and opioid systems may occur peripherally.     

Knockout Corner: Neurobehavioural consequences of a serotonin 5-HT(2C) receptor gene mutation

Studies employing nonselective serotonin 5-HT(2C) receptor agonists and antagonists have implicated this receptor subtype in many of the actions of serotonin. To further examine the function of this receptor, 5-HT(2C) receptor mutant mice were generated; studies of these animals reveal pleiotropic neurobehavioural effects of the mutation. Three examples are described: (1) Mutants exhibit chronically elevated food intake and the development of an obesity syndrome during the 'middle-age' portion of their lifespan. Their potential utility as a model of human obesity is further indicated by their enhanced sensitivity to high-fat feeding, leading to the development of type 2 diabetes. (2) 5-HT(2C) receptor mutants also display infrequent and sporadic spontaneous seizures. Further studies suggested the presence of globally enhanced neuronal network excitability in these mice. These findings raise the possibility that 5-HT(2C) receptors mediate a role for serotonin in the suppression of seizure activity. (3) Behavioural analysis of mutant mice revealed abnormal performance in a spatial learning task and altered exploratory behaviour, associated with perturbed long-term potentiation restricted to the dentate gyrus perforant path synapse. Taken together, the above findings implicate 5-HT(2C) receptors in the serotonergic regulation of feeding, neuronal network excitability, and hippocampal function.     

Dopamine D2 receptor mediation of the discriminative stimulus properties of LY 171555 (quinpirole)

The mechanisms subserving the behavioral effects of the putatively selective dopamine D2 agonist LY 171555 (0.025 mg/kg) were analyzed in rats (N = 23) using a two-lever, water-reinforced drug discrimination task. Substitution (generalization) tests showed that the DA agonist apomorphine mimicked LY 171555 while the selective D1 agonist SKF 38393 did not. When given in combination with the training drug, haloperidol but not the D1 antagonist Sch 23390 dose dependently blocked the LY 171555 cue; given alone, Sch 23390 mimicked LY 171555 and haloperidol elicited responding on the saline-appropriate lever. These results suggest that stimulus properties of LY 171555 are mediated primarily by D2-containing neuronal systems but that the effects of stimulating either D1 or D2 receptor subtypes in vivo are complex and interdependent.     

Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors

The synthesis and monoamine transporter activity of additional members of a series of 3,4-disubstituted piperidines (truncated analogues of the WIN series) are described. All members of this series were prepared from arecoline hydrobromide in optically pure form and were evaluated for their ability to inhibit high affinity uptake of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) into rat brain nerve endings (synaptosomes). Most of the compounds prepared in this series are reasonably potent DAT inhibitors (K(i) values of 4-400 nM) and have selectivity for the 5-HT transporter relative to both the NE transporter (3-9-fold) and to the DAT ( approximately 25-fold). In the present series, (-)-methyl 1-methyl-4beta-(2-naphthyl)piperidine-3beta-carboxylate (6) was found to be the most potent piperidine-based ligand, exhibiting K(i)'s of 21 nM and 7.6 nM at the DAT and 5-HTT, respectively. While the 5-HTT activity of compound 6 is comparable to that of the antidepressant medication fluoxetine, it is less selective. As is apparent from the data presented, the naphthyl substituted piperidines 6-9, which differ in their stereochemistry, show different degrees of selectivity for the three transporters. Consistent with results reported in the literature for the tropane analogues, removal of the methyl group from the nitrogen atom of 9 leads to a further enhancement in 5-HTT activity. To examine the in vivo effects of these piperidines, preliminary behavioral screening was carried out on piperidine 14. Despite its 2.5-fold greater DAT activity compared to cocaine, piperidine 14 was found to be about 2. 5-fold less potent in increasing distance traveled in mice. However, consistent with its DAT activity, piperidine 14 was found to be about 2.5-fold more potent than cocaine in enhancing stereotypic movements. Further studies of these piperidine-based ligands may provide valuable insights into the pharmacological mechanisms underlying the enhancement in distance traveled versus stereotypic movements. The present results have important implications for better understanding the structural motifs required in the design of agents with specific potency and selectivity at monoamine transporters.     

Dual activation by lisuride of central serotonin 5-HT(1A) and dopamine D(2) receptor sites: drug discrimination and receptor binding studies

To investigate central serotonergic (5-HT) and dopaminergic (DA) actions of lisuride, the discriminative properties of lisuride (0.05mg/kg, i.p.) in rats were investigated, in addition to the radioligand binding of the compound to 5-HT and DA receptor subtypes. Lisuride was found to possess high affinities for 5-HT(1A) receptor sites (Ki=0.5nM) and D(2) receptor sites (Ki=2.0nM). The autoradiographic binding pattern of 4nM [(3)H]lisuride in rat brain showed high densities of sites displaceable by the 5-HT(1A) agonist 8-OH-DPAT in hippocampus, lateral septal nucleus and amygdala, as well as those displaceable by the D(2) antagonist sulpiride in striatum, nucleus accumbens and olfactory tubercle. In drug discrimination tests, the mixed, D(1)/D(2) agonist apomorphine, the partial D(2) receptor agonists (-)-3-PPP and terguride and the 5-HT(1A) agonist 8-OH-DPAT substituted for lisuride. The D(1) agonist SKF38393, the D(1) antagonist SCH23390, the D(2) antagonist sulpiride, the 5HT(1B) agonist m-CPP and the 5-HT(2) agonist DOI were not generalized to the lisuride cue. In antagonism tests, the D(2) antagonist haloperidol and the 5-HT antagonist methysergide both induced partial but significant antagonism to the lisuride cue, but the D(1) antagonist SCH23390 did not. These results indicate that discriminative stimulus properties of lisuride are mediated by the dual activation of 5-HT(1A) and D(2) receptor sites in brain.     

N-modified analogues of cocaine: synthesis and inhibition of binding to the cocaine receptor.

Cocaine methiodide (2), N-norcocaine (1b), N-benzyl-N-norcocaine (1c), and N-nor-N-acetylcocaine (1d) were synthesized and evaluated for their ability to inhibit binding of [3H]-3 beta-(4-fluorophenyl)tropane-2 beta-carboxylic acid methyl ester (WIN 35,428) to the cocaine receptor. The study showed that removal of the N-methyl group to give 1b, or replacement with the larger N-benzyl group to give 1c, has a relatively small effect on binding potency. In contrast, replacement of the N-methyl group by the acetyl moiety to give 1d, or the addition of a methyl group to give 2, reduces affinity for the receptor by a large factor. In order to gain preliminary information concerning the importance of the nitrogen location on the tropane ring system, the receptor binding affinity of 8-methyl-8-azabicyclo[3.2.1]octan-3 beta-ol benzoate (5, beta-tropacocaine) was compared to that of the isomeric 6-methyl-6-azabicyclo[3.2.1]octan-3 beta-ol benzoate (4d). The fact that both compounds have similar binding affinities for the cocaine receptor suggests that 3 beta-(benzoyloxy)-6-methyl-6-azabicyclo[3.2.1] octane-2-carboxylic acid methyl ester, which is isomeric with cocaine, may possess binding potency similar to cocaine.