Inotropic beta-blocking potency (pA2) and partial agonist activity of propranolol, practolol, sotalol and acebutolol

The beta-blocking potencies (pA2 values) and cumulative dose responses of the direct effects of dl-propranolol, practolol, acebutolol and sotalol have been characterised in respect of the mechanical performance of isolated cat papillary muscle preparations. pA2 values calculated from antagonism of each of the drugs to the inotropic effect of isoprenaline at 29 degrees C were: dl-propranolol 8.3, practolol 5.6, acebutolol 7.5 and sotalol 4.8. The responses in reserpinized muscles were similar to those in non-reserpinized preparations. dl-Propranolol at concentrations of 10(-5) and 10(-4) M depressed peak developed force (DF) and rate of force development (+dF/dt) by 20% and 60% respectively, with similar but smaller changes in maximum unloaded shortening velocity ('Vmax'). Practolol and sotalol increased DF and +dF/dt by less than 10% at 10(-5) M and by 10-20% at 10(-4) M, with similar but smaller changes in Vmax. Sotalol induced prolonged biphasic contractions at 10(-4) M. Acebutolol had no effect on DF, +dF/dt, or Vmax. Time to peak force and half isometric relaxation time were not altered by any drug. Practolol and acebutolol, generally considered to have partial agonist activity, exerted this to a negligible degree in respect of inotropic effect at less than or equal to 10(-5) M.     

Schild (apparent pA2) analysis of a kappa-opioid antagonist in Planaria

Previous investigators have provided radioimmunological and immunocytochemical evidence for an enkephalinergic (opioid) system in Planaria and described naloxone-sensitive qualitative behavioral responses to κ-opioid receptor agonists. We report the application of Schild-analysis to the antagonism of a selective κ agonist (U-50,488H) by a selective κ antagonist (nor-BNI) in a quantitative in vivo endpoint. The results provide further evidence of a κ-opioid-like receptor in planarians.     

Construction of antagonist dose-response curves for estimation of pA2-values by Schild-plot analysis and detection of allosteric interactions.

1. One aim of this paper is to show an alternative approach for the determination of antagonist affinity estimates, KB and pA2, by construction and evaluation of antagonist dose-response curves (DRCs), using the curve-fitting programme, ALLFIT. 2. Parallel antagonist DRCs were derived by vertical analysis of families of conventional agonist DRCs in the presence and absence of an antagonist at a certain agonist concentration above its ED50. The latter represents a chosen, i.e. fixed dose-ratio (DR). The antagonist concentration that reduces an agonist effect to its Emax/2 was termed Bx. It corresponds to B, the fixed antagonist concentration, tested to obtain DR-1, conventionally. 3. The dissociation constant was calculated as KB = Bx/DR-1, analogous to the conventional approach (KB = B/DR-1). Likewise, pA2-values were estimated by plotting log Bx, obtained by the alternative approach, vs log (DR-1) in an 'alternative Schild plot'. 4. Experimental agonist DRCs from our laboratory and from the literature were analysed and KB- and pA2-values obtained by the alternative approach were compared with those obtained by the conventional method. The results showed a very good agreement (correlation) between the pA2-values obtained by either method (slope = 1.02, r = 0.99, n = 9), in agreement with theoretical DRCs. 5. Besides estimation of KB and pA2, antagonist DRCs were also evaluated qualitatively. The most important finding was that allosteric antagonists or competitive antagonists with an allosteric component, such as gallamine, showed a significant reduction in the maximum of the antagonist DRCs (Imax). The evaluation of antagonist DRCs appears to be a sensitive procedure to detect allosteric interactions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence for intrinsic behavioural activity of the benzodiazepine antagonist, Ro15-1788, in male mice

It would be predicted that putative benzodiazepine should be released under anxiety-provoking conditions and that behavioural changes should be observed following pretreatment with selective antagonists of the benzodiazepine receptor. To test this hypothesis, adult male albino mice were briefly exposed to a novel, brightly-illuminated arena during the dark phase of their LD cycle. Under these test conditions, Ro15-1788 (10 mg/kg) enhanced total rearing whilst, a 5-10 mg/kg, it significantly altered the normal pattern of rearing over the test session. However, at the highest dose tested (20 mg/kg), such behavioural changes were no longer apparent. A similar, though non-significant, trend was observed for locomotor activity. These data, the first to demonstrate-low-dose intrinsic activity of Ro15-1788 in mice, suggest that benzodiazepine antagonists may prove to be powerful tools in the study of the behavioural significance of the benzodiazepine receptor.     

Selectivity and potency of 2-alkyl analogues of the alpha 2-adrenoceptor antagonist idazoxan (RX 781094) in peripheral systems.

The profiles of four analogues of idazoxan have been examined at alpha-adrenoceptors and the results compared to those obtained with idazoxan and yohimbine. The compounds possessed either a methyl (RX 801079), ethyl (RX 811033), n-propyl (RX 811054) or isopropenyl (RX 811005) group at the two position of idazoxan. The rank order of antagonist potency against UK-14,304 at prejunctional alpha 2-adrenoceptors of the rat isolated vas deferens was RX 811054 greater than RX 811033 greater than idazoxan greater than RX 811005 greater than yohimbine = RX 801079. All compounds were competitive antagonists. The rank order of antagonist potency against noradrenaline at postjunctional alpha 1-adrenoceptors of the rat isolated anococcygeus muscle was RX 811054 = RX 811033 = idazoxan = yohimbine greater than RX 811005 = RX801079. All compounds were competitive antagonists. The rank order of alpha-adrenoceptor selectivity (alpha 2/alpha 1) was RX 811005 greater than RX 801079 greater than RX 811054 greater than RX 811033 greater than idazoxan greater than yohimbine. In pithed rats, intravenous administration of all compounds fully reversed the prejunctional alpha 2-adrenoceptor agonist effects of clonidine and guanabenz on electrically-induced contractions of the vas deferens and anococcygeus muscle respectively. In pithed rats the rank order of antagonist potency against UK-14,304 at cardiac prejunctional alpha 2-adrenoceptors was RX 811054 greater than RX 811033 greater than idazoxan greater than yohimbine greater than RX 811005 greater than RX 801079. In contrast, the rank order of antagonist potency against cirazoline pressor effects (vascular postjunctional alpha 1-adrenoceptors) was RX 811054 greater than RX 811033 greater than yohimbine greater than idazoxan greater than RX 811005 greater than RX 801079. The rank order of alpha 2-adrenoceptor selectivity was RX 811033 = RX 801079 = RX 801005 greater than RX 811054 greater than idazoxan greater than yohimbine. Although idazoxan produced contractions of the anococcygeus muscle and increased blood pressure in pithed rats, three of the analogues (RX 811005, RX 801079 and RX 811033) were inactive. In conclusion, alkyl substitution in the 2-position of idazoxan can enhance either alpha 2-adrenoceptor antagonist potency or selectivity or both and furthermore, the weak partial alpha 1-adrenoceptor agonist properties of idazoxan can be removed.     

Bradyzide, a potent non-peptide B(2) bradykinin receptor antagonist with long-lasting oral activity in animal models of inflammatory hyperalgesia

Bradyzide is from a novel class of rodent-selective non-peptide B(2) bradykinin antagonists (1-(2-Nitrophenyl)thiosemicarbazides). Bradyzide has high affinity for the rodent B(2) receptor, displacing [(3)H]-bradykinin binding in NG108-15 cells and in Cos-7 cells expressing the rat receptor with K(I) values of 0.51+/-0.18 nM (n=3) and 0.89+/-0.27 nM (n=3), respectively. Bradyzide is a competitive antagonist, inhibiting B(2) receptor-induced (45)Ca efflux from NG108-15 cells with a pK(B) of 8.0+/-0.16 (n=5) and a Schild slope of 1.05. In the rat spinal cord and tail preparation, bradyzide inhibits bradykinin-induced ventral root depolarizations (IC(50) value; 1.6+/-0.05 nM (n=3)). Bradyzide is much less potent at the human than at the rodent B(2) receptor, displacing [(3)H]-bradykinin binding in human fibroblasts and in Cos-7 cells expressing the human B(2) receptor with K(I) values of 393+/-90 nM (n=3) and 772+/-144 nM (n=3), respectively. Bradyzide inhibits bradykinin-induced [(3)H]-inositol trisphosphate (IP(3)) formation with IC(50) values of 11.6+/-1.4 nM (n=3) at the rat and 2.4+/-0.3 microM (n=3) at the human receptor. Bradyzide does not interact with a range of other receptors, including human and rat B(1) bradykinin receptors. Bradyzide is orally available and blocks bradykinin-induced hypotension and plasma extravasation. Bradyzide shows long-lasting oral activity in rodent models of inflammatory hyperalgesia, reversing Freund's complete adjuvant (FCA)-induced mechanical hyperalgesia in the rat knee joint (ED(50), 0.84 micromol kg(-1); duration of action >4 h). It is equipotent with morphine and diclofenac, and 1000 times more potent than paracetamol, its maximal effect exceeding that of the non-steroidal anti-inflammatory drugs (NSAIDs). Bradyzide does not exhibit tolerance when administered over 6 days. In summary, bradyzide is a potent, orally active, antagonist of the B(2) bradykinin receptor, with selectivity for the rodent over the human receptor. British Journal of Pharmacology (2000) 129, 77 - 86     

Design,synthesis, and SAR of tachykinin antagonists: modulation of balance in NK(1)/NK(2) receptor antagonist activity

Through optimization of compounds based on the dual NK(1)/NK(2) antagonist ZD6021, it was found that alteration of two key regions could modulate the balance of NK(1) and NK(2) potency. Substitution of the 2-naphthalene position in analogues of ZD6021 resulted in increased NK(1) potency and thus afforded NK(1) preferential antagonists. Alterations of the piperidine region could then increase NK(2) potency to restore dual NK(1)/NK(2) selectivity. Through these efforts, three novel receptor antagonists from a single chemically related series were identified; two are dual NK(1)/NK(2) antagonists, and the third is an NK(1) preferential antagonist. In this paper, the factors affecting the balance of NK(1) and NK(2) selectivity in this series are discussed and the in vitro and in vivo properties of the novel antagonists are described.     

桑白皮醇提取物对白三烯拮抗活性的研究(2)

目的对本实验室自行制备的桑白皮醇提取物 (MA)进行了抗白三烯作用的研究。方法通过整体实验 ,研究样品对白三烯D4(LTD4)引起的微血管渗漏 ,LTD4、组胺引起支气管收缩的影响。结果该提取物对LTD4引起豚鼠呼吸道微血管渗漏有明显抑制作用 ,且与选择性白三烯受体拮抗剂普仑司特 (Pranlukast)对呼吸道的作用相类似。同时对白三烯及组胺引起支气管痉挛也具有一定的改善作用 ,显示出与普仑司特不同的作用特点。结论桑白皮醇提取物具有白三烯拮抗活性 ,提示其抗哮喘作用可能与此有关。     

Effects of the 5-HT(6) receptor antagonist, SB-271046, in animal models for schizophrenia

The 5-HT(6) receptor is targeted by several new antipsychotics such as clozapine, olanzapine, and sertindole. We studied the effect of SB-271046 [5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide], a specific 5-HT(6) receptor antagonist, in three models for the positive symptoms of schizophrenia---D-amphetamine-induced hyperactivity, and D-amphetamine- or phencyclidine (PCP)-disrupted prepulse inhibition (PPI). We also tested this compound in a model for the negative symptoms of schizophrenia, PCP-disrupted social interaction (SIT) in rats. Induction of side effects by this compound was evaluated by testing its potency to reduce spontaneous motility, and to induce catalepsy in rats. The effect of SB-271046 was compared to clozapine in all models tested. This study showed that SB-271046 had no beneficial effect in PCP-disrupted SIT. However, SB-271046 dose-dependently normalised D-amphetamine-disrupted PPI, but did not reverse PCP-disrupted PPI. In addition, SB-271046 did not antagonise D-amphetamine-induced hyperactivity. Thus, this specific 5-HT(6) receptor antagonist was associated with a clear positive outcome in only one model for the positive symptoms of schizophrenia, and had no beneficial effect in the model for negative symptoms. Consequently, it is clear that SB-271046 is not expected to have an antipsychotic efficacy, at least when given as monotherapy.     

A thermodynamic approach to problems of drug antagonism. Measurements of the parameters of affinity (pA2) of antihistaminics and a beta-haloalkylamine under varying experimental conditions

Two measurements of pA₂ (in equilibrium and at the receptor site) are described for both diphenhydramine (Benadryl) and phenoxybenzamine (Dibenzyline). For diphenhydramine, after washing out the preparation, there is a spontaneous recovery with a rapid decrease of pA₂ (at the receptor site) to 0, though for phenoxybenzamine the preparation remains at a high level of inhibition for several hours, provided the temperature is kept at 37°C. Such a conditioned allowed a measurement of the affinity parameter (pA₂ = ?log K_i) at different temperatures, from 40°C down to 2–4°C. By using a classical Arrhenius plot it was possible to calculate enthalpies (?ΔH) and entropies (ΔS) of formation of the alleged bindings of phenoxybenzamine with the histamine H₁-receptor which was found to depend strongly upon temperature. Above 20°C the enthalpy ΔH = ?21,494.8 cal/°K was significant and large enough to suggest a covalent or ionic binding, with a negative entropy of formation. Below 20°CΔH = ?3,461.04 e.u. was low and non-significant, with a positive entropy of formation. The conclusion was drawn that at low temperature the binding is probably entropy driven and depends more upon hydrophobic interactions of the antagonist with the receptor site.     

2-Alkyl analogue of idazoxan (RX 781094) with enhanced antagonist potency and selectivity at central alpha 2-adrenoceptors in the rat.

Four 2-alkyl (methyl, ethyl, n-propyl and isopropenyl) analogues of idazoxan (RX 781094) have been synthesized and assessed in terms of their central alpha 2/alpha 1-adrenoceptor selectivity and alpha 2-adrenoceptor antagonist potency using both in vitro and in vivo tests in the rat. In cortical binding assays using [3H]-idazoxan and [3H]-prazosin, idazoxan had a 5 times greater alpha 2/alpha 1-selectivity than yohimbine. The 2-alkyl substituted analogues all showed improved selectivity, being between 17 and 29 times more selective than yohimbine for [3H]-idazoxan binding sites. In terms of central antagonist potency in vivo, the most favourable substitutions were 2-ethyl (RX 811033) and 2-n-propyl (RX 811054). Compared with yohimbine, these analogues were, respectively, 36 and 18 times more potent intravenously and 5 and 7.5 times more potent orally in their antagonism of guanoxabenz-induced mydriasis in the pentobarbitone-anaesthetized rat. All the analogues had a duration of action similar to that of idazoxan, which was significantly shorter than that of yohimbine. The results indicate that introduction of alkyl groups in the 2-position of idazoxan greatly increases the alpha 2/alpha 1-adrenoceptor selectivity as measured in binding studies. Improved alpha 2-adrenoceptor affinity and antagonist potency were particularly associated with the 2-ethyl and 2-n-propyl analogues.     

Design, synthesis, and calcium channel antagonist activity of new 1,4-dihydropyridines containing 4-(5)-chloro-2-ethyl-5-(4)-imidazolyl substituent

A series of dialkyl, dicycloalkyl, and diaryl ester analogues of nifedipine, in which the ortho-nitro phenyl group at position 4 is replaced by the 4-(5)-chloro-2-ethyl-5-(4)-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonists using the high K+ contraction of guinea pig ileal longitudinal smooth muscle. The results for the symmetrical ester series showed that increasing the length of the chain in C3- and C5-ester substituents increased the activity and the most active compound was the diphenylethyl ester derivative, so it was more active than the reference drug nifedipine. In unsymmetrical diester series, when R1 is methyl or ethyl, increasing lipophilic properties in the R substituent, increased the activity. The most active compounds were methyl/phenethyl and ethyl/phenethyl ester derivatives, being slightly more active than nifedipine.     

Effects of anticholinesterase drugs tacrine and E2020, the 5-HT(3) antagonist ondansetron, and the H(3) antagonist thioperamide, in models of cognition and cholinergic function

This study presents a comparison between two inhibitors of acetylcholinesterase, tacrine and E2020 (Donepezil), the 5-HT(3) receptor antagonist ondansetron, and the H(3) receptor antagonist thioperamide, in models of cholinergic function and cognition in male, Lister hooded rats. The cognitive tests used were an operant VI20 task, the delayed match to position task (short-term memory) and the 5-choice serial reaction time task (attention). Scopolamine (SCOP) (0.075mg/kg s.c.) was utilised in both the short-term memory and attention tasks to impair performance. Both tacrine (1-30mg/kg) and E2020 (1-10mg/kg) similarly produced overt cholinomimetic signs of likely central origin (hypothermia, tremor), although tacrine produced more profound peripheral cholinomimetic signs (miosis, secretory signs) than E2020. Tacrine (30mg/kg) and E2020 (10mg/kg) reduced the number of reinforcements gained in the VI20 schedule. Similarly, both drugs attenuated the SCOP-impairment models in the short-term memory and attention tasks (1-3mg/kg). Ondansetron (10ng/kg-1mg/kg) and thioperamide (0.2-10mg/kg) failed to elicit overt cholinomimetic signs or influence the number of food reinforcements gained in the VI20 schedule. Neither ondansetron nor thioperamide attenuated the SCOP-induced impairment in either cognitive task. From the present studies, both E2020 and tacrine showed a similar behavioural profile in the models used, although E2020 was about three times more potent. Furthermore, E2020 but not tacrine appeared to show some discrimination in eliciting central and peripheral cholinomimetic signs. The failure of ondansetron and thioperamide to reverse a SCOP-induced deficit in these models is discussed.     

The anxiolytic-like activity of GR159897, a non-peptide NK2 receptor antagonist,in rodent and primate models of anxiety

The non-peptide NK₂ receptor antagonist, GR159897, was evaluated in two putative models of anxiety, the mouse light-dark box and the marmoset human intruder response test. Effects were compared to the structurally dissimilar NK₂ antagonist, (±) SR48968 and the benzodiazepines, diazepam and chlordiazepoxide. GR159897 (0.0005–50 µg/kg SC) caused significant and dose-dependent increases in the amount of time mice spent in the more aversive light compartment of the light-dark box, with no effect on locomotor activity. (±)SR48968 (0.0005–0.5 µg/kg SC) and diazepam (1–1.75 mg/kg SC), also increased time spent in the light compartment, without effect on locomotor activity. In the marmoset human intruder response test, GR159897 (0.2–50 µg/kg SC) significantly increased the amount of time marmosets spent at the front of the cage during confrontation with a human observer (threat). Similar effects were produced by (±)SR48968 (10–50 µg/kg SC) and chlordiazepoxide (0.3–3.0 mg/kg SC). These results provide further evidence, in both rodent and primate species, for the ability of NK₂ antagonists to restore behaviours which have been suppressed by novel aversive environments. Such effects indicate that NK₂ antagonists may have anxiolytic activity.     

Aporphines. 50. Kinetics of solvolysis of N-(2-chloroethyl)norapomorphine, an irreversible dopamine receptor antagonist

The rates and mechanism of solvolysis of (-)-N-(2-chloroethyl)norapomorphine (NCA, 1c) in aqueous solution have been examined by reversed-phase liquid chromatography (HPLC) to follow the levels of starting material and products. The first-order rate constants for aziridinium ion formation at 25 and 37 degrees C at pH 7.0 are 0.024 and 0.096 min-1, respectively. Determination of the first-order rate constant for the disappearance of NCA as a function of pH has allowed the calculation of an approximate pKa of 6.3 for the tertiary amine, while the influence of reaction conditions (e.g., pH, buffer salt and concentration, and added nucleophiles) on product distribution support the view that NCA solvolysis proceeds through an intermediate aziridinium ion. Application of the HPLC procedure allowed us to observe simultaneously the loss of NCA and the appearance of an intermediate and multiple products at trace levels; it also permitted the facile isolation and subsequent identification of small amounts of hydrolysis products. At pH 7, maximum aziridinium concentration is reached only after 10 min at 37 degrees C and at 25 degrees C after 1 h. Increased temperatures and pH facilitate the rate of aziridinium ion formation, as well as of non-dopamine antagonist solvolysis products. The significance of these findings, including the ease with which buffer ions add to the intermediate ion, are discussed in relation to the use of NCA and its tritiated isomer, [3H]NCA, in dopamine receptor studies.     

Effects of the serotonin 5-HT(2) antagonist, ritanserin, and the serotonin 5-HT(1A) antagonist, WAY 100635, on cocaine-seeking in rats

Manipulations of serotonergic systems have been shown to modify many of the behavioral effects of cocaine. It was recently demonstrated that serotonin (5-HT) depletions produced by inhibition of tryptophan hydroxylase reduced cocaine-seeking in an animal model. The present study was designed to determine whether pretreatment with specific 5-HT antagonists might also decrease cocaine-seeking. The effect of pretreatment with the 5-HT(2) antagonist, ritanserin (0.0, 1.0, or 10.0 mg/kg), or the 5-HT(1A) antagonist, WAY 100635 (0. 0, 0.1, 0.3, or 1.0 mg/kg), on cocaine (5.0, 10.0, or 20.0 mg/kg)-produced reinstatement of extinguished drug-taking behavior was measured. Although ritanserin was ineffective, WAY 100635 attenuated cocaine-produced reinstatement in a dose-dependent manner. These effects of WAY 100635 appeared to be specific since responding maintained by saccharin self-administration remained high following pretreatment with 0.3 or 1.0 mg/kg WAY 100635. These data suggest a role of 5-HT(1A), but not 5-HT(2), receptors in cocaine-seeking.     

Evidence for accelerated desensitisation of 5-HT(2C) receptors following combined treatment with fluoxetine and the 5-HT(1A) receptor antagonist, WAY 100,635, in the rat

Both pre-clinical and clinical studies suggest that additional treatment with 5-HT(1A) receptor antagonists may accelerate the antidepressant efficacy/onset of selective serotonin re-uptake inhibitors (SSRIs). Given that chronic SSRI treatment has been shown to desensitise 5-HT(2C) receptor mediated responses, we have used the rat social interaction test to determine if combined treatment with WAY 100,635, a selective 5-HT(1A) receptor antagonist, will accelerate this effect. In pairs of unfamiliar rats, acute administration of the 5-HT(2C) receptor agonist m-chlorophenylpiperazine (mCPP) or fluoxetine decreased the time spent in social interaction, responses which were reversed by the 5-HT(2C/2B) receptor antagonists SB 200646A and SB 221284. Similar reductions in social interaction were observed in rats treated with fluoxetine (10 mg/kg, i.p. daily) for 4, 7 and 14 days but was no longer apparent after 28 days of treatment. In contrast, only 7 days of combined treatment with WAY 100,635 (1 mg/kg/s.c./day) and fluoxetine were needed to reverse this response. The decrease in social interaction induced by an acute challenge of mCPP (1 mg/kg, i. p.) was also reduced after 6 days co-treatment with WAY 100,635 and fluoxetine. Thus, WAY 100,635 accelerates SSRI-induced desensitisation of 5-HT(2C) receptors, suggesting that this response might contribute towards the therapeutic effects of SSRIs in man.     

Effects of the 5-HT(7) receptor antagonist SB-258741 in animal models for schizophrenia

The 5-HT(7) receptor is targeted by several new antipsychotics such as clozapine and risperidone. We studied the effect of R-(+)-1-(toluene-3-sulfonyl)-2-[2-(4-methylpiperidin-1-yl)ethyl]-pyrrolidine (SB-258741), a specific 5-HT(7) receptor antagonist, in three models for positive symptoms, D-amphetamine-induced hyperactivity and D-amphetamine- and phencyclidine (PCP)-disrupted prepulse inhibition (PPI) in rats, with the aim of investigating the role of this receptor in the clinical effect of antipsychotics. We also tested this compound in a model for negative symptoms, PCP-disrupted social interaction (SIT) in rats. Induction of side effects by this compound was evaluated by testing its potency to reduce spontaneous motility and to induce catalepsy in rats. The effect of SB-258741 was compared to risperidone in all models. This study showed that SB-258741 had no beneficial effect on PCP-disrupted SIT. SB-258741 did not reverse D-amphetamine-disrupted PPI; however, it dose-dependently normalised PCP-disrupted PPI. SB-258741 antagonised D-amphetamine-induced hyperactivity but reduced motility of rats at similar doses. Thus, this specific 5-HT(7) receptor antagonist brought a clear positive outcome in only one model for positive symptoms of schizophrenia and had no beneficial effect in the model for negative symptoms. Consequently, it is clear that SB-258741 affects the PPI phenomenon but is not expected to have an antipsychotic effect on its own in clinic.     

Antidepressant activity of the adenosine A2A receptor antagonist,istradefylline (KW-6002) on learned helplessness in rats

Rationale

Istradefylline, an adenosine A_2A receptor antagonist, improves motor function in animal models of Parkinson’s disease (PD) and in patients with PD. In addition, some A_2A antagonists exert antidepressant-like activity in rodent models of depression, such as the forced swim and the tail suspension tests.

Objective

We have investigated the effect of istradefylline on depression-like behaviors using the rat learned helplessness (LH) model.

Results

Acute, as well as chronic, oral administration of istradefylline significantly improved the inescapable shock (IES)-induced escape deficit with a degree of efficacy comparable to chronic treatment with the tricyclic antidepressant desipramine and the selective serotonin (5-HT) reuptake inhibitor, fluoxetine. Both the A₁/A_2A receptor nonspecific antagonist theophylline and the moderately selective antagonist CGS15943, but not the A₁ selective antagonist DPCPX, ameliorated the IES-induced escape deficit. The enhancement of escape response by istradefylline was reversed by a local injection of the A_2A specific agonist CGS21680 either into the nucleus accumbens, the caudate-putamen, or the paraventricular nucleus of the hypothalamus, but not by the A₁ specific agonist R-PIA into the nucleus accumbens. Moreover, neither the 5-HT_2A/2C receptor antagonist methysergide or the adrenergic α 2 antagonist yohimbine, nor the β-adrenergic antagonist propranolol, affected the improvement of escape response induced by istradefylline.

Conclusions

Istradefylline exerts antidepressant-like effects via modulation of A_2A receptor activity which is independent of monoaminergic transmission in the brain. Istradefylline may represent a novel treatment option for depression in PD as well as for the motor symptoms.