Depressive disorders are heterogeneous diseases, and the complexity of symptoms has led to the formulation of several aethiopathological hypotheses. This heterogeneity may account for the following open issues about antidepressant therapy: (i) antidepressants show a time lag between pharmacological effects, within hours from acute drug administration, and therapeutic effects, within two-four weeks of subchronic treatment; (ii) this latency interval is critical for the patient because of the possible further mood worsening that may result in suicide attempts for the seemingly ineffective therapy and for the apparent adverse effects; (iii) and only 60-70 % of treated patients successfully respond to therapy. In this review, the complexity of the biological theories that try to explain the molecular mechanisms of these diseases is considered, encompassing (i) the classic "monoaminergic hypothesis" alongside the updated hypothesis according to which long-term therapeutical action of antidepressants is mediated by intracellular signal transduction pathways and (ii) the hypothalamic-pituitary-adrenal axis involvement. Although these models have guided research efforts in the field for decades, they have not generated a compelling and conclusive model either for depression pathophysiology or for antidepressant drugs' action. So, other emerging theories are discussed: (iii) the alterations of neuroplasticity and neurotrophins in selective vulnerable cerebral areas; (iv) the involvement of inflammatory processes; (v) and the alterations in mitochondrial function and neuronal bioenergetics. The focus is put on the molecular and theoretical links between all these hypotheses, which are not mutually exclusive but otherwise tightly correlated, giving an integrated and comprehensive overview of the neurobiology of depressive disorders.
Two decades of investigations have failed to unequivocally clarify the functions and the molecular nature of imidazoline-2 receptors (I2R). However, there is robust pharmacological evidence for the functional modulation of monoamino oxidase (MAO) and other important enzyme activities by I2 site ligands. Some compounds of this class proved to be active experimental tools in preventing both experimental pain and opioid tolerance and dependence. Unfortunately, even though these compounds bind with high potency to central I2 sites, they fail to represent a valid clinical opportunity due to their pharmacokinetic, selectivity or side-effects profile. This paper presents the preclinical profile of a novel I2 ligand (2-phenyl-6-(1H-imidazol-1yl) quinazoline; [CR4056]) that selectively inhibits the activity of human recombinant MAO-A in a concentration-dependent manner. A sub-chronic four day oral treatment of CR4056 increased norepinephrine (NE) tissue levels both in the rat cerebral cortex (63.1% ±4.2%; P < 0.05) and lumbar spinal cord (51.3% ± 6.7%; P < 0.05). In the complete Freund’s adjuvant (CFA) rat model of inflammatory pain, CR4056 was found to be orally active (ED50 = 5.8 mg/kg, by mouth [p.o.]). In the acute capsaicin model, CR4056 completely blocked mechanical hyperalgesia in the injured hind paw (ED50 = 4.1 mg/kg, p.o.; ED100 = 17.9 mg/kg, p.o.). This effect was dose-dependently antagonized by the non-selective imidazoline I2/α2 antagonist idazoxan. In rat models of neuropathic pain, oral administration of CR4056 significantly attenuated mechanical hyperalgesia and allodynia. In summary, the present study suggests a novel pharmacological opportunity for inflammatory and/or neuropathic pain treatment based on selective interaction with central imidazoline-2 receptors.
Novel AT(1) receptor antagonists bearing substituted 4-phenylquinoline moieties instead of the classical biphenyl fragment were designed and synthesized as the first step of an investigation devoted to the development of new antihypertensive agents and to the understanding of the molecular basis of their pharmacodynamic and pharmacokinetic properties. The newly synthesized compounds were tested for their potential ability to displace [(125)I]Sar(1),Ile(8)-Ang II specifically bound to AT(1) receptor in rat hepatic membranes. These AT(1) receptor binding studies revealed nanomolar affinity in several of the compounds under study. The most potent ligands 4b,t were found to be equipotent with losartan and possessed either a 3-tetrazolylquinoline or a 2-amino-3-quinolinecarboxylic moiety, respectively. Moreover, some selected compounds were evaluated for antagonism of Ang II-induced contraction in rabbit aortic strips, and the most potent compounds in the binding test 4b,t were slightly more potent than losartan in inhibiting Ang II-induced contraction. Finally, the most relevant structure-affinity relationship data were rationalized by means of computational studies performed on the isolated ligands as well as by computational simulations on the ligands complexed with a theoretical AT(1) receptor model.
The 4-phenylquinoline fragment of novel AT(1) receptor antagonists 4 based on imidazo[4,5-b]pyridine moiety was replaced by 4-phenylisoquinolinone (compounds 5) or 1-phenylindene (compounds 6) scaffolds to investigate the structure-activity relationships. Binding studies showed that most of the synthesized compounds display high affinity for the AT(1) receptor. Because of the in vitro high potency of carboxylic acids 5b,f, they were evaluated in permeability (in Caco-2 cells) and in pharmacokinetic studies in comparison with quinoline derivatives 4b,i,j,k. The studies showed that these compounds are characterized by rapid excretion, low membrane permeability, and low oral bioavailability. The structure optimization of the indene derivatives led to compounds 6e,f possessing interesting AT(1) receptor affinities. Optimization produced polymerizing AT(1) receptor ligand 6c, which forms a thermoreversible polymer (poly-6c) and is released from the latter by a temperature-dependent kinetics. The results suggest the possibility of developing novel polymeric prodrugs based on a new release mechanism. Finally, a set of 34 AT(1) receptor antagonists was used as a new test for the evaluation of the predictive capability of the previously published qualitative and quantitative pharmacophore models.
Although bortezomib (BTZ) is the frontline treatment for multiple myeloma, its clinical use is limited by the occurrence of painful peripheral neuropathy, whose treatment is still an unmet clinical need. Previous studies have shown chronic BTZ administration (0.20 mg/kg intravenously three times a week for 8 weeks) to female Wistar rats induced a peripheral neuropathy similar to that observed in humans. In this animal model of BTZ-induced neurotoxicity, the present authors evaluated the efficacy of CR4056, a novel I2 ligand endowed with a remarkable efficacy in several animal pain models. CR4056 was administered in a wide range of doses (0.6–60 mg/kg by gavage every day for 2–3 weeks) in comparison with buprenorphine (Bupre) (28.8 μg/kg subcutaneously every day for 2 weeks) and gabapentin (Gaba) (100 mg/kg by gavage every day for 3 weeks). Chronic administration of BTZ reduced nerve conduction velocity and induced allodynia. CR4056, Bupre, or Gaba did not affect the impaired nerve conduction velocity. Conversely, CR4056 dose-dependently reversed BTZ-induced allodynia (minimum effective dose 0.6 mg/kg). The optimal dose found, 6 mg/kg, provided a constant pain relief throughout the treatment period and without rebound after suspension, being effective when coadministered with BTZ, starting before or after allodynia was established, or when administered alone after BTZ cessation. A certain degree of tolerance was seen after 7 days of administration, but only at the highest doses (20 and 60 mg/kg). Bupre was effective only acutely, since tolerance was evident from the fourth day onwards. Gaba showed a significant activity only at the fourth day of treatment. CR4056, over the range of concentrations of 3–30 μM, was unable to hinder BTZ cytotoxicity on several tumor cell lines, which could indicate that this substance does not directly interfere with BTZ antitumor activity. Therefore, CR4056 could represent a new treatment option for BTZ-induced neuropathic pain.
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