Caffeine, an adenosine A 1 , A 2A , and A 2B receptor antagonist, is frequently used as an adjuvant analgesic in combination with nonsteroidal anti-inflammatory drugs or opioids. In this study, we have examined the effects of novel specific adenosine receptor antagonists in an acute animal model of nociception. Several A 2B -selective compounds showed antinociceptive effects in the hot-plate test. In contrast, A 1 -and A 2A -selective compounds did not alter pain thresholds, and an A 3 adenosine receptor antagonist produced thermal hyperalgesia. Evaluation of psychostimulant effects of these compounds in the open field showed only small effects of some antagonists at high doses. Coadministration of low, subeffective doses of A 2B -selective antagonists with a low dose of morphine enhanced the efficacy of morphine. Our results indicate that analgesic effects of caffeine are mediated, at least in part, by A 2B adenosine receptors.Caffeine has intrinsic antinociceptive properties and is frequently used as an adjuvant analgesic drug (Malec and Michalska, 1988;Sawynok and Yaksh, 1993). Although it is thought that caffeine analgesia is produced, at least in part, through adenosine receptor antagonism, it is unclear which receptor subtypes are involved. The adenosine receptor family comprises four subtypes: A 1 , A 2A , A 2B , and A 3 (Fredholm et al., 2001). They are widely distributed in the CNS and peripheral tissues. The A 1 receptors are found in high density in the brain (cortex, cerebellum, and hippocampus) and the dorsal horn of the spinal cord, and at lower levels in other brain regions and in peripheral tissues (Rivkees et al., 1995;Fredholm et al., 2001). The A 2A receptors show a more restricted expression pattern in the CNS with high levels in the striatum, nucleus accumbens, and olfactory tubercle (Ongini and Fredholm, 1996). In the periphery, A 2A receptors are highly expressed in spleen, thymus, leukocytes, and blood platelets (Ongini and Fredholm, 1996). A 2B and A 3 receptors are widely distributed, but have a low density in the CNS (Dixon et al., 1996). In the periphery, A 2B receptors are highly expressed in the large intestine, on mast cells and hematopoietic cells (Feoktistov and Biaggioni, 1995). A 3 receptors show a species-dependent distribution: in rats, testis and mast cells express A 3 receptors in high density (Salvatore et al., 1993), whereas humans exhibit high A 3 receptor expression in the lung and in cells of the immune system (Salvatore et al., 1993).A 1 receptors can couple to G i , thus inhibiting the formation of cAMP, whereas stimulation of A 2 receptors, which bind to G s leads to an increase in adenylate cyclase activity (Fredholm et al., 2001).

Alzheimer’s disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Similar to acetylcholinesterase, butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its enzymatic activity increases with the disease progression, thus classifying BChE as a viable therapeutic target in advanced AD. Potent, selective and reversible human BChE inhibitors were developed. The solved crystal structure of human BChE in complex with the most potent inhibitor reveals its binding mode and provides the molecular basis of its low nanomolar potency. Additionally, this compound is noncytotoxic and has neuroprotective properties. Furthermore, this inhibitor moderately crosses the blood-brain barrier and improves memory, cognitive functions and learning abilities of mice in a model of the cholinergic deficit that characterizes AD, without producing acute cholinergic adverse effects. Our study provides an advanced lead compound for developing drugs for alleviating symptoms caused by cholinergic hypofunction in advanced AD.

The aim of this study was to further characterize pharmacological properties of two phenylpiperazine derivatives: 1-{2-[2-(2,6-dimethlphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazynine hydrochloride (HBK-14) and 2-[2-(2-chloro-6-methylphenoxy)ethoxy]ethyl-4-(2- methoxyphenyl)piperazynine dihydrochloride (HBK-15) in radioligand binding and functional in vitro assays as well as in vivo models. Antidepressant-like properties were investigated in the forced swim test (FST) in mice and rats. Anxiolytic-like activity was evaluated in the four-plate test in mice and elevated plus maze test (EPM) in rats. Imipramine and escitalopram were used as reference drugs in the FST, and diazepam was used as a standard anxiolytic drug in animal models of anxiety. Our results indicate that HBK-14 and HBK-15 possess high or moderate affinity for serotonergic 5-HT2, adrenergic α1, and dopaminergic D2 receptors as well as being full 5-HT1A and 5-HT7 receptor antagonists. We also present their potent antidepressant-like activity (HBK-14—FST mice: 2.5 and 5 mg/kg; FST rats: 5 mg/kg) and (HBK-15—FST mice: 1.25, 2.5 and 5 mg/kg; FST rats: 1.25 and 2.5 mg/kg). We show that HBK-14 (four-plate test: 2.5 and 5 mg/kg; EPM: 2.5 mg/kg) and HBK-15 (four-plate test: 2.5 and 5 mg/kg; EPM: 5 mg/kg) possess anxiolytic-like properties. Among the two, HBK-15 has stronger antidepressant-like properties, and HBK-14 displays greater anxiolytic-like activity. Lastly, we demonstrate the involvement of serotonergic system, particularly 5-HT1A receptor, in the antidepressant- and anxiolytic-like actions of investigated compounds.

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Abstract:The aim of this research was to assess the antinociceptive activity of the transient receptor potential (TRP) channel TRPV1, TRPM8, and TRPA1 antagonists in neurogenic, tonic, and neuropathic pain models in mice. For this purpose, TRP channel antagonists were administered into the dorsal surface of a hind paw 15 min before capsaicin, allyl isothiocyanate (AITC), or formalin. Their antiallodynic and antihyperalgesic efficacies after intraperitoneal administration were also assessed in a paclitaxel-induced neuropathic pain model. Motor coordination of paclitaxeltreated mice that received these TRP channel antagonists was investigated using the rotarod test. TRPV1 antagonists, capsazepine and SB-366791, attenuated capsaicin-induced nociceptive reaction in a concentration-dependent manner. At 8 µg/20 µl, this effect was 51% (P<0.001) for capsazepine and 37% (P<0.05) for SB-366791. A TRPA1 antagonist, A-967079, reduced pain reaction by 48% (P<0.05) in the AITC test and by 54% (P<0.001) in the early phase of the formalin test. The test compounds had no influence on the late phase of the formalin test. In paclitaxel-treated mice, they did not attenuate heat hyperalgesia but N-(3-aminopropyl)-2-{ [(3-methylphenyl)methyl]oxy}-N-(2-thienylmethyl) benzamide hydrochloride salt (AMTB), a TRPM8 antagonist, reduced cold hyperalgesia and tactile allodynia by 31% (P<0.05) and 51% (P<0.01), respectively. HC-030031, a TRPA1 channel antagonist, attenuated tactile allodynia in the von Frey test (62%; P<0.001). In conclusion, distinct members of TRP channel family are involved in different pain models in mice. Antagonists of TRP channels attenuate nocifensive responses of neurogenic, tonic, and neuropathic pain, but their efficacies strongly depend on the pain model used.

Depression is a serious global illness, becoming more and more common in developed countries. Because of specific symptoms it is considered as a leading cause of disability all over the world with a high death factor due to suicides. There are many antidepressants used in the therapy, but still more than 30% of patients do not respond to the treatment. The heterogeneous nature of the illness and its complex, unclear aetiology may be responsible for these difficulties. Next to the main monoaminergic hypothesis of depression there are also many other approaches connected with the pathophysiology of the disease, including hypothalamic-pituitary-adrenal axis dysregulation, dopaminergic, cholinergic, glutamatergic or GABA-ergic neurotransmission. Nevertheless, it can be unambiguously stated that serotonergic, noradrenergic and dopaminergic systems are precisely connected with pathogenesis of depression, and should be therefore considered as valuable targets in patients' treatment. Bearing that in mind, this review presents the role of serotonergic, adrenergic and dopaminergic receptors in antidepressant-like effect.

The results obtained in the present study suggest that tiagabine, apart its anticonvulsant effect, has anxiolytic-like, sedative and antidepressant-like properties. In view of this, it can be potentially used in the treatment of anxiety and mood disorders.