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Abstract: The mechanism of the antidepressant-like activity of the selective 5-hydroxytryptamine1B (5-HT1B) receptor agonist 5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine (CP 94253) was studied in the forced swimming test in mice. CP 94253 administered intraperitoneally at a single dose of 5 mg/kg potently shortened the immobility time of mice. The anti-immobility effect of CP 94253 was wholly blocked by the selective 5-HT1B receptor antagonist N-[3-(2-dimethylamino)ethoxy-4-methoxyphenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1′-biphenyl)-4-carboxamide (SB 216641, 5 mg/kg), the dopamine D2-like receptor antagonist sulpiride (50 mg/kg) and the α2-adrenoceptor antagonist idazoxan (2 mg/kg), but was not modified in animals with a lesion of the 5-HT system produced by p-chlorophenylalanine (p-CPA, 3×300 mg/kg). The obtained results suggest that the anti-immobility effect of CP 94253 is mediated by activation of 5-HT1B receptors—most probably located postsynaptically and/or as heteroreceptors, and that the dopamine and the noradrenaline systems are involved in this action. [Copyright &y& Elsevier]

We examined the potential anxiolytic-like activity of (−)-N-phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxamide (PHCCC), an allosteric modulator of metabotropic glutamate4 receptors (mGlu4), after administration into the basolateral amygdala, using the conflict drinking Vogel test in rats as a model. The results indicate that PHCCC, but not 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt), the selective antagonist of group mGlu1 receptors, showed significant, dose-dependent anticonflict effects without affecting the threshold current or water intake. The results indicate that positive allosteric modulation of mGlu4 receptors may be a useful therapeutic approach to anxiety. [Copyright &y& Elsevier]

Abstract: Introduction of 1,4-disubstituted cyclohexane ring in the structure of flexible long chain arylpiperazines resulted in linearly constrained, potent serotonin (5-HT)1A ligands. In order to trace structure–intrinsic activity relationships in this group, a new series of 1-substituted 4-(4-arylpiperazin-1-yl)cyclohexane derivatives with different cyclic imide/amide termini, and their flexible, tetramethylene analogues were synthesized and pharmacologically evaluated for 5-HT1A receptors. In vitro binding experiments revealed that all the compounds were potent 5-HT1A receptor agents (K i =1.9–74nM). Some derivatives tested additionally showed also high affinity for α1-adrenergic receptors (K i =2.9–101nM) and for 5-HT7 receptors. Functional in vivo examination revealed that rigid ligands with o-OCH3 group in the aryl moiety and cyclic imide system in the opposite terminal behaved like postsynaptic 5-HT1A receptor antagonists. On the other hand, unsubstituted, m-Cl, or m-CF3 substituted derivatives as well as those with cyclic amide group in the terminal fragment exhibited agonistic or partial agonistic activity. Three out of four derivatives tested, that is, postsynaptic 5-HT1A antagonists 9 and 10, and partial agonist 16, showed anxiolytic-like activity in the conflict drinking (Vogel) test in rats. [Copyright &y& Elsevier]

Abstract: A series of new 3-[4-(4-arylpiperazinyl)-butyl]-β-tetralonohydantoins (8a–13a) were synthesized. The compounds exhibited high affinity for 5-HT1A receptors (K i =6 to 55 nM) combined with moderate-to-high 5-HT2A receptor affinities (K i =45 to 213 nM). The results of in vivo studies indicated that of the compounds tested, 3-[4-(4-phenylpiperazinyl)-butyl-β-tetralonohydantoin (8a) showed features of full (pre- and postsynaptic) 5-HT1A receptor agonists, whereas compounds 9a–13a behaved like antagonists of postsynaptic 5-HT1A receptors; additionally, compound 13a produced an effect characteristic of presynaptic 5-HT1A receptor agonists. Moreover, compounds 8a and 10a–13a exhibited properties of 5-HT2A receptor antagonists. Due to the most interesting 5-HT1A/5-HT2A functional profile compounds 8a and 13a were further tested for their potential psychotropic activity. In fact, compound 8a (but not 13a) showed diazepam—like anxiolytic activity and behaved like a weak antidepressant. [Copyright &y& Elsevier]

Abstract: Starting with the structure of potent 5-HT1A ligands, that is, MM77 [1-(2-methoxyphenyl)-4-(4-succinimidobutyl)piperazine, 4] and its constrained version 5 (MP349), previously obtained in our laboratory, a series of their direct analogues with differently substituted aromatic ring (R=H, m-Cl, m-CF3, m-OCH3, p-OCH3) were synthesized. The flexible and the corresponding 1e,4e-disubstituted cyclohexane derivatives were designed in order to investigate the influence of rigidification on 5-HT1A affinity, selectivity for 5-HT2A, 5-HT7, D1, and D2 binding sites and functional profile at pre- and postsynaptic 5-HT1A receptors. The new compounds 19–25 were found to be highly active 5-HT1A receptor ligands (Ki=4–44nM) whereas their affinity for other receptors was: either significantly decreased after rigidification (5-HT7), or controlled by substituents in the aromatic ring (α1), or influenced by both those structural modifications (5-HT2A), or very low (D2, Ki=5.3–31μM). Since a distinct disfavor towards rigid compounds was observed for 5-HT7 receptors only, it seems that the bioactive conformation of chain derivatives at those sites should differ from the extended one. Several in vivo models were used to asses functional activity of 19–25 at pre- (hypothermia in mice) and postsynaptic 5-HT1A receptors (lower lip retraction in rats and serotonin syndrome in reserpinized rats). Unlike the parent antagonists 4 and 5, all the new derivatives tested were classified as partial agonists with different potency, however, similar effects were observed within pairs (flexible and rigid) of the analogues. The obtained results indicated that substitution in the aromatic ring, but not spacer rigidification, controls the 5-HT1A functional activity of the investigated compounds. Moreover, an o-methoxy substituent in the structure of 5 seems to be necessary for its full antagonistic properties. Of all the new compounds studied, trans-4-(4-succinimidocyclohexyl)-1-(3-trifluoromethylphenyl)piperazine 24 was the most potent 5-HT1A receptor ligand in vitro (Ki=4nM) and in vivo, with at least 100-fold selectivity for the other receptors tested. [Copyright &y& Elsevier]

GABAergic hypothesis of anxiety was introduced many years ago, however, a limited number of supporting data were accumulated so far and the role of GABA(B) receptors in behavioral processes related to the anxiety disorders has not been resolved. In the present study, we examined anxiolytic activity of CGP 36742, a potent and selective GABA(B) receptor antagonist, in rodent tests/models. We have demonstrated that CGP 36742 (30 mg/kg) is active in several animal tests detecting anxiolytic activity (the elevated plus-maze, conflict drinking test and four-plate test). Moreover, we examined the effects of another antagonist--CGP51176 and agonist--CGP 44532 of GABA(B) receptor in the four-plate test in mice. CGP 51176 (5 or 8 mg/kg) was inactive, while CGP 44532 (0.125 mg/kg) exhibited anxiogenic-like effect. These preclinical data further implicate GABA(B) receptor function in anxiety, and support the GABAergic hypothesis of this disorder.

The present study was designed to evaluate the effects of BIBO 3304 in the Vogel's conflict drinking test and in the water intake test in non-deprived rats after injection of the drug into the basolateral nucleus of the amygdaloid complex. BIBO 3304 was given at the doses of 25, 100 and 200 pmol/0.5 microl/site. We investigated also the effect of 5-hydroxytryptophan (5-HTP), given intraperitoneally at a dose of 20 mg/kg, which was used as a positive control in the water intake test. Water consumption was measured 1, 2, 4, 6 and 24 h after drug administration. We found that water intake was increased both after 5-HTP and BIBO 3304 administration.

Two series of novel 4-ethyl- or 4-propyl-1-arylpiperazines (5-12) with the 4,4'-disubstituted diphenylmethylamino (series a) or the diphenylmethoxy (series b) terminal fragment were synthesized and evaluated for their binding affinity at 5-HT1A and 5-HT2A receptors. The influence of the introduction of 4-methyl, 4-chloro or 4-fluoro substituents at both phenyl rings of that terminal moiety on in vitro and in vivo 5-HT1A receptor activity of those modified compounds was discussed. Compounds 5a, 6a, 9a-12a, 5b, 6b, 9b, 11b and 12b displayed high to fairly high affinity for 5-HT1A receptors (Ki = 2.4-72 nM). Compounds of both series showed low or very low 5-HT2A receptor affinity (Ki = 155-5400 nM). Amines 5a, 6a, 11a, and their ether analogs 5b, 6b and 11b, also possessed high or moderate alpha(1)-adrenoceptor affinity (K(i) = 6-104 nM). The functional activity of compounds 5a, 6a, 9a-12a, 5b, 8b, 9b, 11b and 12b was tested in vivo in the commonly used animal models. The majority of those ligands behaved like 5-HT1A receptor antagonists, their influence on the pre- and/or postsynaptic sites being diverse, though. They exhibited characteristics of partial agonists of postsynaptic 5-HT1A receptors (11a), of weak antagonists of pre- and postsynaptic sites (12a, 9b), of antagonists of presynaptic (5a) or of antagonists of postsynaptic 5-HT(1A) receptors (9a, 10a, 5b, 8b, 11b and 12b) while, 6a was devoid of functional activity at those receptors. The above findings indicate that introduction of 4-methyl, 4-chloro or 4-fluoro substituents to the diphenylmethyl part of the 1-(2-methoxyphenyl)piperazines tested in vivo may modify their 5-HT1A receptor functional activity.

Several lines of evidence indicate that inhibition of the metabotropic glutamate (mGlu) receptor 5 produces anxiolytic-like effects in rodents. Peptide neurotransmitter neuropeptide Y (NPY) produces an anxiolytic effect in rats after intraventricular or intra-amygdalar administration. Many classes of anxiolytic drugs exert their effect through the GABA-benzodiazepine (BZD) receptor complex. Therefore, in the present study we have investigated whether the anxiolytic action of MPEP (2-methyl-6-(phenylethynyl)pyridyne), an mGlu5 receptor antagonist, is mediated by a mechanism involving either the GABA-BZD receptor complex or NPY receptor. In the behavioral studies, the anxiolytic activity of MPEP (10 mg/kg, i.p.) was examined using plus-maze test. The BZD antagonist flumazenil (10 mg/kg, i.p.) was given to one group of rats and Y1 receptor antagonist BIBO 3304 (((R)-N-[[4-(aminocarbonylaminomethyl) phenyl] methyl]-N2-(diphenylacetyl)-argininamide trifluoroacetate)3304) (200 pmol/site, intra-amygdala) to the other. It was found that anxiolytic effects of MPEP were not changed by flumazenil, but were abolished by BIBO 3304. Immunohistochemical studies showed a high density of mGlu5 receptor immunoreactivity (IR) in the amygdala. The effect of MPEP on NPY expression in the amygdala was studied using immunohistochemistry (IH) and radioimmunoassay (RIA). Both methods showed a diminution of NPY IR expression, to about 43% (IH) or 81% (RIA) of the control level after multiple administrations, but we observed an increase up to 148% of the control after single MPEP administration. These effects may suggest a release of NPY from nerve terminals after MPEP administration. Our results indicate that the anxiolytic action of MPEP is conveyed through NPY neurons with the involvement of Y1 receptors in the amygdala and that BZD receptors do not significantly contribute to these effects.

A series of 15 new 2-H- and 2-substituted 5-[omega-[4-(2-methoxyphenyl)-piperazinyl]-alkyl]-1,2,3,4-tetrahydro-gamma-carboline derivatives were prepared, and their affinity for 5-HT1A and 5-HT2A serotonin receptors was determined. Most of those hybrid compounds were found to bind with high affinity to 5-HT1A sites (Ki < 50 nM; 2d, 3a, 3b, 3d, 3e, 4b, 4d, 4e) and moreover two of them (4d, 4e) were mixed 5-HT1A/5-HT2A ligands. The results of a lower lip retraction test in rats indicated that the 2-acetyl derivative with a dimethylene spacer (2d) had features of a postsynaptic 5-HT1A receptor agonist, whereas its analogues with longer chains (3d and 4d) behaved like antagonists. Both 5-HT2A receptor ligands (4d, 4e) at high doses inhibited the (+/-)-DOI-induced head twitches in mice and were classified as weak antagonists of those receptors.