Drugs which influence serotonin transporter and serotonergic receptors: Pharmacological and clinical properties in the treatment of depression.

Depression is nowadays a major contributor to global burden of disease. The most commonly prescribed drugs influence monoaminergic pathways, mainly concentrating on serotonin. Unfortunately, there are several drawbacks associated with these drugs, namely late onset of action, risk of suicide and adverse effects: mainly nausea, vomiting and sexual dysfunction. Therefore there is still need for new drugs with possibly high efficacy and fewer side effects. In this paper selected compounds which inhibit serotonin reuptake by acting on the serotonin transporter (SERT) and various serotoninergic receptors are presented. We also discuss the ways in which their mechanism of action can be modified to improve pharmacological profile. Here, we focus on describing drugs' potency, efficacy and adverse effects. Additional applications, apart from depression, are also discussed.

Novel renin inhibitors containing derivatives of N-alkylleucyl-ß-hydroxy-γ-amino acids.

In search for new drugs lowering arterial blood pressure, which could be applied in anti-hypertensive therapy, research concerning agents blocking of renin-angiotensin-aldosteron system has been conducted. Despite many years of research conducted at many research centers around the world, aliskiren is the only one renin inhibitor, which is used up to now. Four novel potential renin inhibitors, having structure based on the peptide fragment 8-13 of human angiotensinogen, a natural substrate for renin, were designed and synthesized. All these inhibitors contain unnatural moieties that are derivatives of N-methylleucyl-ß-hydroxy-γ-amino acids at the P2-P1' position: 4-[N-(N-methylleucyl)-amino]-3-hydroxy-7-(3-nitroguanidino)-heptanoic acid (AHGHA), 4-[N-(N-methylleucyl)-amino]-3-hydroxy-5-phenyl-pentanoic acid (AHPPA) or 4-[N-(N-methylleucyl)-amino]-8-benzyloxycarbonylamino-3-hydroxyoctanoic acid (AAHOA). The previously listed synthetic ß-hydroxy-γ-amino acids constitute pseudodipeptidic units that correspond to the P1-P1' position of the inhibitor molecule. An unnatural amino acid, 4-methoxyphenylalanin (Phe(4-OMe)), was introduced at the P3 position of the obtained compounds. Three of these compounds contain isoamylamide of 6-aminohexanoic acid (ε-Ahx-Iaa) at the P2'-P3' position. The proposed modifications of the selected human angiotensinogen fragment are intended to increase bioactivity, bioavailability, and stability of the inhibitor molecule in body fluids and tissues. The inhibitor Boc-Phe(4-OMe)-MeLeu-AHGHA-OEt was obtained in the form of an ethyl ester. The hydrophobicity coefficient, expressed as log P varied between 3.95 and 8.17. In vitro renin inhibitory activity of all obtained compounds was contained within the range 10(-6)-10(-9) M. The compound Boc-Phe(4-OMe)-MeLeu-AHPPA-Ahx-Iaa proved to be the most active (IC50 = 1.05 × 10(-9) M). The compounds Boc-Phe(4-OMe)-MeLeu-AHGHA-Ahx-Iaa and Boc-Phe(4-OMe)-MeLeu-AHPPA-Ahx-Iaa are resistant to chymotrypsin.

Cytisine basicity, solvation, logP, and logD theoretical determination as tool for bioavailability prediction.

Cytisine, an α4ß2 nicotinic receptor partial agonist, is a plant alkaloid widely used as a smoking cessation agent. Despite long history of use, knowledge on pharmacokinetics of cytisine still demands an extension. This work is aimed at theoretical determination of physicochemical parameters that affect the bioavailability of cytisine. The acidic dissociation constant, Gibbs free energy of solvation in water and n-octanol as well as n-octanol/water partition coefficient and n-octanol/water distribution coefficient of cytisine were calculated as quantities corresponding to its solubility and permeability. Cytisine structure was optimized with several quantum chemical methods-ab initio: HF and MP2, and DFT functionals (B3LYP, B3LYP-D3, CAM-B3LYP, M06-2X, TPSS, VSXC) with 6-311++G(d,p) basis set. Solvation of cytisine in water and n-octanol was determined with the SMD continuum model. It was shown that lipophilicity of cytisine depends on the pH of an environment. Protonated cytisine, the most populated state under acidic conditions, is characterized by enhanced hydrophilicity. Then neutral cytisine, dominating in a basic environment, demonstrates more lipophilic character. It appears that cytisine is very well soluble in the gastrointestinal (GI) tract fluids. Then the distribution of cytisine ought to occur very rapidly. However, permeability of cytisine through the mucous membrane of the GI tract may be limited, leading to the diminished bioavailability.

Physicochemical properties of lomefloxacin, levofloxacin, and moxifloxacin relevant to the biopharmaceutics classification system.

The aim of this investigation was to identify the impact of physicochemical properties of three fluoroquinolones (second, third, and fourth generation) on bioavailability in relation to the Biopharmaceutics Classification System (BCS) by in silico and in vitro methods. These properties were estimated by analyzing the electrostatic potential pattern and values of the free energy of solvation as well as the distribution coefficients and true partition coefficients of the studied compounds. This study was based on theoretical quantum-chemical methods and the in vitro shake-flask technique with two immiscible phases (n-octanol and phosphate buffer) as well as the experimental potentiometric method to estimate protonation macro- and micro-constants. Properties identified in the in vitro and in silico studies were similar and indicated high lipophilic properties of the studied molecules as well as their good solubility in a polar medium. It appears that both the theoretical methods and simple in vitro studies are useful tools for predicting the bioavailability of medicinal substances based on the BCS principles.

Intrinsic activity and comparative molecular dynamics of buspirone analogues at the 5-HT(1A) receptors.

In CNS, the 5-hydroxytryptamine(1A) (5-HT(1A)) receptors exist in two different populations with different behavioural and physiological effects: (1) somatodendritic autoreceptors located pre-synaptically of 5-HT containing neurons and (2) receptors located post-synaptic to 5-HT containing neurons. Clinical studies have shown that 5-HT(1A) partial agonists have anxiolytic properties, while antagonists of pre-synaptical autoreceptors shorten the onset time of selective serotonin reuptake inhibitors (SSRIs). In the present study, the pre- and post-synaptic activity of structural analogues of buspirone was evaluated in animal models. A three dimensional model of the 5-HT(1A) receptor was used to study their interaction modes and helical displacements upon receptor binding. The predicted receptor-ligand interactions indicated similarities in the receptor binding modes for all buspirone analogues, and no clear relationship between receptor contact residues and activity at pre- and post-synaptic receptors. Comparative molecular dynamics (MD) simulations for 650ps indicated that pre-synaptic antagonistic behaviour is connected to large displacements of transmembrane helix (TMH) 7 upon binding, while pre-synaptic agonistic behaviour is connected to large displacements of TMH2 and small displacements of TMH7. Post-synaptic partial agonist behaviour is connected to large displacements of TMH4 and TMH5 upon binding, while post-synaptic antagonists only slightly displace these helices.