Interaction of β-adrenoceptor agonists with the serotonergic system in rat brain

Summary The effect of -adrenoceptor agonists on the behavioral effect of l-5-HTP in rats and mice was studied. All -agonists potentiated the behavioral syndrome elicited by l-5-HTP. However no indication for a correlation between their potencies to stimulate peripheral beta-receptors and their potencies to enhance l-5-HTP effects was found. The potentiating effect of salbutamol in rats was intensified by the MAO A inhibitor clorgyline, completely inhibited by (±)-propranolol and partly inhibited by WB-4101, while practolol was without effect. Lesions of 5-HT pathways by i.c.v. injections of 5,7-DHT impaired the potentiating effect of salbutamol in rats. In contrast, 6-OHDA lesions or alphamethyl-p-tyrosine pretreatment were without effect. A central site of action of salbutamol is suggested by the fact that it intensified l-5-HTP effects also after i.c.v. administration. Therefore the results suggest that salbutamol facilitates 5-HT transmission in rat brain probably via stimulation of central beta receptors.A part of this study was presented at the meeting of the Deutsche Pharmakologische Gesellschaft in Mainz, March 18–21, 1980     

Structural analysis by the comparative molecular field analysis method of the affinity of β-adrenoreceptor blocking agents for 5-HT1A and 5-HT1B receptors

The affinities of 17β-adrenoreceptor antagonists for 5-HT_1A and 5-HT_1B receptors were evaluated in binding assays. A large range of K_i values (2–10,000 nM) was observed and ortho or meta substitution of the aromatic ring carrying the amino chain was implicated in the high affinity K_i values, whereas para substitution elicited a dramatic drop in activity. These variations were analyzed with two molecular design tools: the active analogue approach (AAA) and the new 3D-QSAR (quantitative structure activity relationship) method, comparative molecular field analysis (CoMFA). The AAA method emphasized, by superimposition of selected conformations of the molecules, the favorable and unfavorable volumes implicated in the receptor recognition. CoMFA generated a linear expression between the biological data and the different values of electrostatic and steric fields surrounding the molecules. It predicted the values of selected molecules but also those of new molecules not included in the study. The excellent accuracy of the prediction revealed the potential of the method for the design of new compounds. CoMFA demonstrated the important contribution of steric parameters, evaluated at 92%, compared to the electrostatic field (evaluated at 8%) to explain the affinity for 5-HT_1A and 5-HT_1B receptors. This study emphasizes also the importance of the occupancy of a hydrophobic pocket in the receptor site located near the area interacting with the aromatic moiety, and subsequently its use for the design of new, potent, specific antagonists of 5-HT_1A and 5-HT_1B receptors.     

(−)Tertatolol is a potent antagonist at pre- and postsynaptic serotonin 5-HT1A receptors in the rat brain

Summary The potential 5-HT_1A antagonist properties of the ß-antagonist tertatolol were assessed using biochemical and electrophysiological assays in the rat. (±) Tertatolol bound with high affinity (K_i = 38 nM) to 5-HT_1A sites labelled by [³H]8-OH-DPAT in hippocampal membranes. The (–)stereoisomer (K_i = 18 nM) was about 50-fold more potent than the (+)stereoisomer (K_i = 864 nM) to inhibit the specific binding of [³H]-8-OHDPAT. As expected of a 5-HT_1A antagonist, (–)tertatolol prevented in a concentration-dependent manner (K_i = 24 nM) the inhibitory effect of 8-OH-DPAT on forskolin-stimulated adenylate cyclase activity in rat hippocampal homogenates. Furthermore in vivo pretreatment with (–)tertatolol (5 mg/kg s.c.) significantly reduced the inhibitory influence of 8-OH-DPAT (0.3 mg/ kg s.c.) on the accumulation of 5-hydroxytryptophan in various brain areas after the blockade of aromatic L-amino acid decarboxylase by NSD-1015 (100 mg/kg i.p.). In vitro (in brainstem slices; K_i 50 nM) and in vivo (in chloral hydrate anaesthetized rats; ID₅₀ 0.40 mg/kg i.v.), (–)tertatolol prevented the inhibitory effects of the 5-HT_1A receptor agonists 8-OH-DPAT, ipsapirone and lesopitron on the firing rate of serotoninergic neurones within the dorsal raphe nucleus. In about 25% of these neurones, the basal firing rate was significantly increased by (–)tertatolol (up to +47% in vitro, and +30% in vivo). These data indicate that (-)tertatolol is a potent competitive antagonist at both pre (in the dorsal raphe nucleus) - and post (in the hippocampus) - synaptic 5-HT_1A receptors in the rat brain.Abbreviations ACSF artificial cerebrospinal fluid - BMY-7378 8-[2-[4(2-methoxy-phenyl)-1-piperazinyl]ethyl]-8-azaspiro-[4,5]-decane-7,9dione - DRN dorsal raphe nucleus - 5-HIAA 5-hydroxyindole acetic acid - 5-HT 5-hydroxytryptamine (serotonin) - 5-HTP 5-hydroxytryptophan - MDL 73005 EF 8-[2-[(2,3-dihydro-1,4-benzodioxin-2-yl)-methylamino]ethyl]-8-azaspiro-[4,5]-decane-7,9-dione, methyl sulfonate - NAN-190 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine - 8-OH-DPAT 8-hydroxy-2-(di-n-propylamino) tetralin - (S)-UH-301 (S)-5-fluoro-8-hydroxy-2-(dipropylamino) tetralin - WAY-100,135 N-tert-butyl-3,4-(2-methoxyphenyl)-piperazin-1-yl-2-phenylpropanamide Correspondence to T. Jolas at the above address     

Irreversible binding of a carbostyril-based agonist and antagonist to the β-adrenoceptor in DDT1 MF-2 cells and rat aorta

1. The chemoreactive ligands 5(2-(((1′-(4′-isothiocyanatophenylamino)thiocarbonyl)-amino)-2-methyl-propyl)amino-2-hydroxypropoxy)-3,4-dihydrocarbostyril (DCITC) and 8-hydroxy-5(2-(((1′-(4′-isothiocya-natophenylamino)thiocarbonyl)amino)-2-methylprop-2-yl)amino-1-hydroxyethyl)-carbostyril (HCITC)were synthesized and shown to be potent irreversible antagonist and agonist ligands, respectively, for the β-adrenoceptor in DDT₁ MF-2 (DDT) cells and the rat isolated aorta.
2. In DDT cell membranes DCITC and HCITC inhibited (−)[¹²⁵I]-iodocyanopindolol (CYP) binding to the β-adrenoceptor with IC₅₀ values of 1.1 and 18 nM, respectively. (−)-Isoprenaline inhibited [¹²⁵I]-CYP binding with an IC₅₀ of 355 nM. Pretreatment of membranes with either chemoreactive ligand produced a time- and concentration-dependent decrease in the β-adrenoceptor content, indicating irreversible receptor binding. DCITC at concentrations up to 10 μM did not stimulate cyclic AMP accumulation in DDT cells nor did it amplify forskolin-stimulated cyclic AMP accumulation.
3. In the rat isolated aorta, DCITC (0.1 μM) did not affect either the phenylephrine-mediated tissue contraction or the acetylcholine-mediated relaxation. DCITC attenuated the maximal (−)-isoprenaline-mediated relaxation of a phenylephrine contracted aorta in a concentration-dependent manner and shifted the dose-response curves for (−)-isoprenaline to the right. The DCITC-induced decrease in maximal response was not reversed by extensive tissue washing. By use of the operational model of agonism, the calculated dissociation constant for (−)-isoprenaline ws 286 nM and the estimated receptor reserve for this agonist was 23% at the maximal response.
4. HCITC and (−)-isoprenaline stimulated cyclic AMP accumulation in DDT cells with pD₂ values (negative logarithm to base 10 of EC₅₀) of 7.95 and 7.97, respectively, and both mediated the same maximal stimulation. In the rat isolated aorta, HCITC produced a concentration-dependent relaxation of the tissue with a pD₂ value of 6.62, whereas the pD₂ for (−)-isoprenaline was 7.03. However, HCITC produced a greater maximal relaxation of the tissue than (−)-isoprenaline. The HCITC-mediated stimulation of cyclic AMP accumulation and relaxation of the isolated tissue were blocked when the β-antagonist propranolol was added concurrently. In contrast, once the HCITC-mediated responses were established, the addition of propranolol did not result in any attenuation indicating that HCITC is an irreversible β-agonist.

     

SDZ 216–525, a selective and potent 5-HT1A receptor antagonist

The pharmacological properties of SDZ 216–525, methyl 4-{4-[4(1,1,3-trioxo-2H,1,2-benzoisothiazol-2-yl)butyl]-1-piperazinyl}1H-indole-2-carboxylate, a new selective and potent 5-HT_1A receptor antagonist, are described in vitro (and comparisons made with those of MDL 73005 and NAN 190, two putative for 5-HT_1A receptor antagonists) and in vivo. In radioligand binding studies, SDZ 216–525 showed high affinity and selectivity for 5-HT_1A sites (pK_D = 9.2) as compared to 5-HT_1B, 5-HT_1C, 5-HT_1D, 5-HT₂ and 5-HT₃ sites (pK_D= 6.0, 7.2, 7.5, 5.2 and 5.4, respectively). The affinity of the compound for α₁, α₂, β₂ and β₂ adrenoceptors. and dopamine D₂ receptors was at least 50–100 times lower than for 5-HT_1A sites. The effects of SDZ 216–525, MDL 73005 and NAN 190 on 5-HT₁ receptor-linked second messengers were characterized in the following tests: inhibition of forskolin-stimulated adenylate cyclase activity in calf hippocampus (5-HT_1A), rat substantia nigra (5-HT_1B) and calf substantia nigra (5-HT_1D) and stimulation of inositol phosphate production in pig choroid plexus (5-HT_1C). SDZ 216–525 potently antagonised the effects of 8-OH-DPAT (8-hydroxy-2[N-diprophyl-amino]-tetralin) on 5-HT_1A receptors (pK_B = 10) and displayed no intrinsic activity in this test, whereas it behaved at best as a weak antagonist on the other receptor models pK_B values < 6.9). NAN 190 also behaved as a potent antagonist at 5-HT_1A receptors (pK_B = 8.7), whereas MDL 73005 displayed potent and nearly full agonism at 5-HT_1A receptors (pEC₅₀ = 7.3, E_max = 92%). Both compounds behaved broadly similarly to SDZ 216–525 in the other models. In vivo, SDZ 216–525 did not induce forepaw treading or flat body posture in lighlty44 reserpinies rats at up to 1 mg/kg s.c., whereas the behavioural responses to a submaximal dose of 8-OH-DPAT (0.25 mg/kg s.c.) were inhibited dose dependently by SDZ 216–525 over the range 0.03−1 mg/kg s.c. Similarly, SDZ 216–525 over the same dose range suppressed dose dependently the hypothermic effects of 8-OH-DPAT. These data demonstrate SDZ 216–525 to be a potent and selective 5-HT_1A receptor antagonist in vitro and in vivo.     

Evidence that ranolazine behaves as a weak β1- and β2-adrenoceptor antagonist in the rat cardiovascular system

The clinical anti-anginal effectiveness of ranolazine is currently being evaluated. However, the mechanism of its anti-ischaemic action is still unclear. The aim of this work was to establish whether ranolazine exerts functional beta-adrenoceptor antagonist activity in the rat cardiovascular system. Radioligand binding studies were performed in rat hearts and guinea-pig lungs for beta1- and beta2-adrenoceptor affinity, respectively. Ranolazine had micromolar affinity for both beta,- and beta2-adrenoceptors (pKi5.8 and 6.3, respectively). Developed tension was measured in isolated rat left atria (electrically driven at 4 Hz) and cumulative concentration/response curves to (+/-)isoprenaline (0.01-1,000 nM) constructed. Ranolazine (0.32-10 microM) surmountably but weakly antagonised isoprenaline-induced positive inotropic responses, with an apparent pA2 of 5.85 (5.69-6.00) and a slope of -0.74 (-0.70 to -0.77). In bivagotomised, atropinised pithed rats, ranolazine per se evoked marked bradycardia at doses above 10 mg/kg i.v. (maximum variation at 80 mg/kg -125+/-15 bpm, n=6, P<0.001) by a mechanism apparently unrelated to blockade of beta1- or beta2-adrenoceptors. Cumulative incremental doses of (+/-)isoprenaline (0.63 ng/kg to 0.16 mg/kg i.v.) administered to pithed rats induced concomitant depressor and chronotropic responses. Animals received either vehicle (saline 0.9% i.v., n=12), atenolol (0.04-2.5 mg/kg i.v., n=6 per dose), ICI 118551 (0.01-0.63 mg/kg i.v., n=6 or 7 per dose), (+/-)propranolol (0.01-0.63 mg/kg i.v., n=6 per dose) or ranolazine (2.5-80 mg/kg i.v., n=6 or 7 per dose) 10 min prior to isoprenaline. Ranolazine dose-dependently and competitively antagonised isoprenaline-induced decreases in diastolic arterial pressure (DAP, dose ratio 12.2 with 80 mg/kg ranolazine) and increases in heart rate (HR, dose ratio 20.3 with 80 mg/kg ranolazine). Collectively, these results demonstrate that ranolazine behaves as a weak beta1- and beta2-adrenoceptor antagonist in the rat cardiovascular system.     

Muscarinic receptor interaction with full and partial β-adrenoceptor agonists in the rat colon strip

Summary -Adrenoceptor agonists inhibit contractile activity in isolated colon strips. In order to demonstrate that -adrenoceptors are located at different functional levels within the colon wall, increasing concentrations of muscarinic agonists were used to interact functionally with the -adrenoceptor-mediated inhibition of spontaneous colon activity. The effects of the full agonists isoprenaline and terbutaline and of the partial agonist prenalterol were functionally antagonized by carbachol (0.03 and 0.3 mol/l) and bethanechol (1,3 and 30 ol/l). This functional antagonism was parallelled by an increase in baseline tension and spontaneous contractile activity of the isolated colon strip. At lower concentrations of carbachol (0.003 and 0.01 ol/l) or bethanechol (0.03 and 0.31 mol/l) no effect on the contractile status of the smooth muscle or on the pD₂-values of the full agonists was seen. However, at these lower concentrations of muscarinic agonists a marked decrease in the maximal inhibitory response to the partial -adrenoceptor agonist prenalterol was demonstrated. The inhibitory response to prenalterol showed a biphasic concentration-response curve. The muscarinic antagonist atropine produced an increase in the maximal response of the high potency component of the concentration-response curve for prenalterol and an increase in the sensitivity to isoprenaline. These results demonstrate the presence of a high cholinergic tone in the colon preparation of a magnitude that clearly reduces the sensitivity to -adrenoceptor agonists. The different responses to full and partial -adrenoceptor agonists in the presence of increasing concentrations of muscarinic agonists may indicate that -adrenoceptors are located on two different functional units within the colon wall.     

The effects of ethanol in combination with the α2-adrenoceptor agonist dexmedetomidine and the α2-adrenoceptor antagonist atipamezole on brain monoamine metabolites and motor performance of mice

The time course of the effects of ethanol alone and in combination with the selective α₂-adrenoceptor agonist dexmedetomidine and the α-adrenoceptor antagonist atipamezole was studied in NIH-Swiss mice. Core body temperature, rotarod performance, motility and changes in the noradrenaline, dopamine, and 5-hydroxytryptamine (5-HT) metabolite contents of different brain parts (limbic forebrain, striatum, lower brainstem, the rest of the forebrain + midbrain and hypothalamus) were measured. Atipamezole (3 mg/kg) attenuated the hypothermia induced by either ethanol (3 g/kg) alone or ethanol in combination with dexmedetomidine (0.3 mg/kg). Atipamezole shortened the duration of the ethanol-impaired and ethanol + dexmedetomidine-impaired rotarod performance. Further, atipamezole prevented the decreased motility due to the combined treatment with ethanol and dexmedetomidine. Ethanol increased 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) values. Dexmedetomidine alone decreased MHPG and 5-hydroxyindoleacetic acid (5-HIAA) concentrations and increased DOPAC and HVA values. Dexmedetomidine combined with ethanol resulted in a further increase in DOPAC and HVA values. Pharmacokinetic parameters did not contribute to this antagonism of ethanol's effects by atipamezole, nor did the antagonism observed in rotarod performance or hypothermia seem to correlate with the changes seen in the brain noradrenaline and dopamine or 5-HT metabolism. In conclusion, these findings suggest that several ethanol effects are not mediated via direct activation of α₂-adrenoceptors, even though some of ethanol's behavioral and physiological effects may be antagonized by coadministration of α₂-adrenoceptor antagonists.     

Sodium ions increase the affinity of clonidine for α1-adrenoceptors in rat brain

Summary ₁-Adrenoceptors in rat brain membranes, labeled by the antagonist [³H] prazosin, increase their affinity for clonidine several-fold when sodium ions are added. The conversion of ₁-adrenoceptors, by sodium ion, into a conformation, which has higher affinity for the agonist clonidine, indicates that these receptors as the ₂-adrenoceptors are modulated by cations in vitro.This is part of the thesis to be presented by R. H. to the Fachbereich Humanmedizin, Justus Liebig-Universität Giessen, FRG, in partial fulfilment of the requirements for a Doctor of Medical Science degree     

Effect of pretreatment with the selective β1-adrenoceptor antagonist bisoprolol on the subsequent cardiovascular actions and β-adrenoceptor subtype specific occupancy of celiprolol in healthy man

Summary The cardiovascular effects at rest and during exercise and ₁- and ₂-adrenoceptor occupancy following a single dose of 1200 mg celiprolol p. o. were investigated in 8 healthy subjects with or without pretreatment with a single dose of 20 mg bisoprolol p. o., using a place-bo-controlled, 2-way cross-over design.The ergometric responses of heart rate (HR) and systolic blood pressure (SBP) after celiprolol were reduced to a similar extent as after bisoprolol, but the cardiovascular function at rest was affected in a different way: there was a rise in HR, clear enhancement of cardiac systolic performance, and a considerable drop in the estimated total peripheral vascular resistance, associated with median ₁-RRA and ₂-RRA occupancies of 88 and 34%, respectively. The cardiovascular effects of celiprolol were not affected by pretreatment with bisoprolol. Celiprolol thus binds extensively to ₁-adrenoceptors, moderately to ₂-adrenoceptors, acts as ₁-adrenergic antagonist (exemplified by the ergometric effects) but has vasodilator, positive chronotropic and cardiac systolic performance enhancing properties, which do not involve either direct or indirect ₁-adrenergic agonism, but which might reflect ₂-adrenergic agonism.     

Evaluation of the effects of dopexamine,a novel DA1 receptor and β2-adrenoceptor agonist,on cardiac function and splanchnic circulation in a canine model of hemorrhagic shock

Summary In the present studies, the efficacy of dopexamine hydrochloride, a novel DA₁-receptor and ₂-adrenoceptor agonist in preventing deterioration of cardiovascular function in a canine model of hemorrhagic shock was investigated. Pentobarbital-anesthetized dogs were allowed to bleed into a height-regulated reservoir and the hypotensive state (about 40 mmHg) was maintained for a period of 150 min. Subsequently, blood was reinfused and recoveries in various hemodynamic variables were monitored for an additional period of 120 min. Either aqueous solvent or dopexamine HCl was randomly selected for i. v. infusion beginning 30 min before reinfusion of the blood and until the termination of the experiment.In the solvent-treated control group, various cardiovascular variables such as cardiac output, stroke volume, celiac and superior mesenteric arterial blood flows progressively declined to 50% or less of the basal values; these changes were associated with sustained increases in the regional as well as systemic vascular resistances. Dopexamine infusion lowered vascular resistances and facilitated recoveries in various hemodynamic variables to 80% to 100% of the basal values after reinfusion of the shed blood. With the exception of a transient inotropic effect during reinfusion in the dopexamine treated group, there were no essential alterations in the myocardial contractility, during the hypotensive state and/or after reinfusion of the blood.Hence, the results indicate that the efficacy of dopexamine to reduce vascular resistance by actions at DA₁-receptors and ₂-adrenoceptors would account for its ability to improve myocardial performance (secondary to reductions in afterload) and restoration of mesenteric and celiac hemodynamics. These salutary effects of dopexamine could be useful in the clinical management of hemorrhagic shock. Correspondence to B. S. Jandhyala at the above address     

Cellular and behavioural effects of a new steroidal inhibitor of the N-methyl-d-aspartate receptor 3α5β-pregnanolone glutamate

Preclinical studies have demonstrated a considerable role for N-methyl-d-aspartate (NMDA) receptors in excitotoxicity and the concurrent neuroprotective effect of NMDA receptor antagonists. Because NMDA receptors are one of the most widespread receptors in the central nervous system, application of their antagonist often leads to serious side effects ranging from motor impairment to induction of schizophrenic-like psychosis. Therefore, we have initiated development and testing of a novel synthetic NMDA receptor antagonist derived from naturally occurring neurosteroids. 20-oxo-5β-pregnan-3α-yl-l-glutamyl-1-ester (3α5βP-Glu) is a novel synthetic steroidal inhibitor of the NMDA receptor. Our results show that 3α5βP-Glu preferentially inhibits tonically activated NMDA receptors, is able to cross the blood brain barrier, does not induce psychotomimetic symptoms (such as hyperlocomotion and sensorimotor gating deficit) and reduced an excitotoxic damage of brain tissue and subsequent behavioural impairment in rats. In particular, 3α5βP-Glu significantly ameliorated neuronal damage in the dentate gyrus and subiculum, and improved behavioural performance in active allothetic place avoidance tasks (AAPA, also known as the carousel maze) after bilateral NMDA-induced lesions to the hippocampi. These findings provide a possible new therapeutic approach for the treatment of diseases induced by NMDA receptor overactivation.     

The effects of chronic dosing on the β1 and β2-adrenoceptor antagonism of betaxolol and atenolol

Summary Six normal subjects were given once daily treatment for 15 days with placebo (PL), betaxolol 10 mg (B10), 40 mg (B40); atenolol 100 mg (A100); and nadolol 40 mg (N40). Measurements of ₁-adrenoceptorblockade (reduction of exercise heart rate) and of ₂-adrenoceptor-blockade (attenuation of isoprenaline induced finger tremor) were made after the first, eighth and fifteenth doses of each drug.Plasma concentrations showed dose related increases between 10 mg and 40 mg doses of betaxolol, and there was significant drug accumulation at steady state compared with after single dosing. The reduction in exercise heart rate (EHR) with B10 was less in comparison with all other treatments.There were no significant differences in effects between single and chronic-dosing for any of the treatments (% reduction EHR compared with placebo, on days 1 and 15): B10 (18.2, 19.0), B40 (28.6, 26.5); A100 (22.7, 23.1); N40 (26.6, 23.8). Dose-ratios for attenuation of isoprenaline-induced finger tremor (IT₁₀₀) were significantly greater with B40 compared with B10 or A100 (no dose-ratio for finger tremor could be calculated for N40).There were no differences between single and chronic-dosing (IT₁₀₀ dose-ratios on days 1 and 15): B10 (3.0, 2.5), B40 (4.4, 5.3); A100 (3.0, 3.0). The attenuation of isoprenaline-induced chronotropic response (IH₂₅) by N40 was significantly greater in comparison with all other treatments. IH₂₅ dose-ratios (on days 1 and 15) were as follows: B10 (2.8, 3.6), B40 (5.1, 5.8); A100 (3.6, 3.6); N40 (19.0, 17.4).Thus, despite drug accumulation after chronic-dosing, there was no evidence of any increase in either ₁ or ₂-adrenoceptor antagonism at steady-state in comparison with after single-dosing. The apparent dissociation between plasma concentration and -adrenoceptor antagonism after chronic-dosing my be a consequence of -adrenoceptor up-regulation, resulting in partial attenuation of -blockade.     

Urapidil and some analogues with hypotensive properties show high affinities for 5-hydroxytryptamine (5-HT) binding sites of the 5-HT1A subtype and for α1-adrenoceptor binding sites

Summary The mechanism responsible for the antihypertensive effect of urapidil is not yet completely understood. Its vasodilator action has been attributed to an antagonism at vascular ₁-adrenoceptors. However, it has been suggested that a central action contributes to the hypotensive effect. Recently, three potent analogues of urapidil have been described which also lower blood pressure by a central mechanism. 5-Hydroxytryptamine (5-HT) receptors of the 5-HT_1A subtype have been implicated with the central control of cardiovascular function. In the present study, the affinities of these urapidil derivatives (5-acetyl, 5-formyl- and 5-methylurapidil) for 5-HT receptors were investigated using ³H-8-hydroxy-2-(di-n-propylamino)tetralin (³H-8-OH-DPAT), ¹²⁵I-iodocyanopindolol (¹²⁵I-ICYP) and ³H-ketanserin for labelling 5-HT_1A, 5-HT_1B and 5-HT₂ binding sites, respectively. ³H-Prazosin and ³H-clonidine were used as selective ₁- and ₂-adrenoceptor radioligands, respectively. Urapidil and its analogues produced half-maximum inhibition of ³H-8-OH-DPAT binding at concentrations of 4 × 10^–9 mol/l to 4 × 10^–7 mol/l with the following order of potency: urapidil < 5-acetyl- < 5-formyl- < 5-methyl-urapidil. Thus, 5-methyl-urapidil is one of the most potent ligands at 5-HT_1A recognition sites known to date. The IC₅₀ values of urapidil and its derivatives for ³H-prazosin binding were in the range of 5 × 10^–8 mol/l to 8 × 10^–7 mol/l (order of potency: urapidil < 5-formyl- < 5-acetyl- 5-methyl-urapidil). The affinity of these analogues for 5-HT_1B, 5-HT₂ and ₂-adrenergic recognition sites was distinctly lower. Urapidil and its congeners clearly discriminate between 5-HT- and between -receptor subtypes. It is postulated that the high affinity for 5-HT_1A receptors as well as for ₁-adrenoceptors is relevant to the hypotensive properties of these compounds. Send offprint requests to G. Groß     

Mecamylamine – a nicotinic acetylcholine receptor antagonist with potential for the treatment of neuropsychiatric disorders

Mecamylamine (Inversine^®), the first orally available antihypertensive agent launched in the 1950s, is rarely used today for hypertension because of its widespread ganglionic side effects at antihypertensive doses (25 – 90 mg/day). However, more recent clinical studies suggest that mecamylamine is effective at much lower doses for blocking the central and peripheral effects of nicotine. Pharmacologically, mecamylamine has been well characterized as a nonselective and noncompetitive antagonist of nicotinic acetylcholine receptors (nAChRs). Because mecamylamine easily crosses the blood – brain barrier at relatively low doses (2.5 – 10 mg), it has been used by several research groups over the past two decades investigating the role of central nAChRs in the etiology and treatment of various neuropsychiatric disorders, including addiction disorders, Tourette's syndrome, schizophrenia and various cognitive and mood disorders. Two independent Phase II clinical trials recently confirmed mecamylamine's hypothesized antidepressant activity and suggest that it may be effective as an augmentation pharmacotherapy for SSRI treatment resistant major depression. These areas of investigation for mecamylamine are reviewed and recommendations for future research directions are proposed.     

α-Adrenergic and 5-HT2-serotonergic effects of some β-phenylethylamines on isolated rat thoracic aorta

• 1.1. 2C-H [2-(2,5-dimethoxyphenyl)ethylamine] (pD₂ = 6.74), TMPEA [2-(2,4,5-trimethoxyphenyl)ethylamine] (pD₂ = 5.83), 2C-D [2-(2,5-dimethoxy-4-methylphenyl)ethylamine] (pD₂ = 5.06), homoveratrylamine [DMPEA, 2-(4,5-dimethoxyphenyl)ethylamine] (pD₂ = 4.46) and homopiperonylamine [MDPEA, 2-(3,4-methylenedioxyphenyl)ethylamine] (pD₂ = 4.19), elicit concentration-dependent contraction of the isolated rat thoracic aorta.
• 2.2. At 9.9 × 10⁻⁶ M, 2C-N [2-(2,5-dimethoxy-4-nitrophenyl)ethylamine] behaves as a competitive antagonist to serotonin in this preparation.
• 3.3. Considering previous results with the structurally related 2C-B [2-(4-bromo-2,5-dimethoxyphenyl)ethylamine], weak or partial agonistic activity or antagonism of aortic contraction appears to be related to psychedelic properties reported in humans for phenylethylamines.