Development of novel multipotent compounds modulating endocannabinoid and dopaminergic systems.

Polypharmacology approaches may help the discovery of pharmacological tools for the study or the potential treatment of complex and multifactorial diseases as well as for addictions and also smoke cessation. In this frame, following our interest in the development of molecules able to modulate either the endocannabinoid or the dopaminergic system, and given the multiple and reciprocal interconnections between them, we decided to merge the pharmacophoric elements of some of our early leads for identifying new molecules as tools able to modulate both systems. We herein describe the synthesis and biological characterization of compounds 5a-j inspired by the structure of our potent and selective fatty acid amide hydrolase (FAAH) inhibitors (3a-c) and ligands of dopamine D or D receptor subtypes (4a,b).

Potency, efficacy, and selectivity of GR64349 at human recombinant neurokinin NK2 and NK1 receptors.

The affinity, potency, efficacy, and selectivity of the NK2 receptor agonist GR64349 ([Lys,Gly,-R-γ-lactam-Leu]NKA(3-10)) at human recombinant NK2 and NK1 receptors was examined. In radioligand binding studies, GR64349 displaced [I]-NKA binding to NK2 receptors with high affinity (pKi 7.77 + 0.

Affinity, potency, efficacy, and selectivity of neurokinin A analogs at human recombinant NK2 and NK1 receptors.

A series of peptide NK2 receptor agonists was evaluated for affinity, potency, efficacy, and selectivity at human recombinant NK2 and NK1 receptors expressed in CHO cells to identify compounds with the greatest separation between NK2 and NK1 receptor agonist activity. Binding studies were performed using displacement of [125I]-NKA binding to NK2 receptors and displacement of [3H]-Septide binding to NK1 receptors expressed in CHO cells. Functional studies examining the increase in intracellular calcium levels and cyclic AMP stimulation were performed using the same cell lines.

1,2,4-Triazolyl 5-Azaspiro[2.4]heptanes: Lead Identification and Early Lead Optimization of a New Series of Potent and Selective Dopamine D3 Receptor Antagonists.

A novel series of 1,2,4-triazolyl 5-azaspiro[2.4]heptanes with high affinity and selectivity at the dopamine (DA) D3 receptor (D3R) is described. Some of these compounds also have high selectivity over the hERG channel and were characterized with respect to their pharmacokinetic properties both in vitro and in vivo during lead identification and early lead optimization phases.

Novel morpholine scaffolds as selective dopamine (DA) D3 receptor antagonists.

A new series of morpholine derivatives has been identified as selective DA D3 receptor antagonists; their in vitro profile and pharmacokinetic data are provided.

Functional and binding kinetic studies make a distinction between OX1 and OX2 orexin receptor antagonists.

In this work the pharmacology and the receptor kinetics of the following orexin receptor antagonists SB-649868, ACT-078573, JNJ-10397049, MK-6096 and Roche-Cp were evaluated at human OX(1) and OX(2) orexin receptors by using functional and receptor binding assays. Kinetic analysis of the unlabeled ligands was carried out by indirect measurement according to the Motulski and Mahan's method as opposed to the direct measure by using labeled test compounds. All compounds antagonized orexin-A-induced inositol 1 phosphate (IP1) accumulation with the following pK(B) values: SB-649868 (OX(1)=9.

Distinct receptor subtypes mediate arginine vasopressin-dependent ACTH release and intracellular calcium mobilization in rat pituitary cells.

In the present study, adrenocorticotropic hormone (ACTH) release and intracellular calcium ([Ca(2+)](i)) increase induced by arginine vasopressin (AVP) were characterized in collagenase-dispersed and 3-day cultured rat anterior pituitary cells. AVP and the selective vasopressin V(1b) receptor agonist, [1-deamino-4-cyclohexylalanine]AVP (d[Cha(4)]AVP) induced ACTH release with nanomolar potencies in both cell preparations, and produced a maximal stimulation that was about 1.5 fold greater in the 3-day cultured cells, indicating that the vasopressin V(1b) receptor-ACTH release pathway is enhanced over time in culture.

In vitro and in vivo characterization of the novel GABAB receptor positive allosteric modulator, 2-{1-[2-(4-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]-2-piperidinyl}ethanol (CMPPE).

There is preclinical evidence supporting the finding that the GABA(B) receptor orthosteric agonist, baclofen, has significant effects on eating behavior suggesting the potential therapeutic application of this compound for the treatment of eating related disorders. However, the wide clinical use of baclofen might be limited by the appearance of sedative and motor impairment effects. The identification of positive allosteric modulators (PAMs) of GABA(B) receptors represents a novel therapeutic approach to reduce the centrally-mediated adverse effects typical of the GABA(B) receptor orthosteric agonist.

Pharmacological characterization of the ghrelin receptor antagonist, GSK1614343 in rat RC-4B/C cells natively expressing GHS type 1a receptors.

A novel growth hormone secretagogues type 1a (GHS1a) receptors antagonist (2R)-N'-[3,5- bis(trifluoromethyl)phenyl]-2-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(3- pyridinyl)ethanohydrazide (GSK1614343) was functionally characterised in rat pituitary adenoma cell line, RC-4B/C endogenously expressing GHS1a receptors. The antagonism profile of GSK1614343 was compared with that of 6-[(4-fluorophenyl)oxy]-2-methyl-3-{[(3S)-1-(1-methylethyl)-3- piperidinyl]methyl}-4(3H)-quinazolinone (YIL-781) another ghrelin receptor antagonist recently published. The activity of both compounds was also evaluated at rat recombinant GHS1a receptors.

Synthesis and pharmacological characterization of constrained analogues of Vestipitant as in vitro potent and orally active NK(1) receptor antagonists.

A focused exploration targeting conformationally restricted analogues of Vestipitant, resulted in the discovery of novel, in vitro potent NK(1) antagonists. In particular, two of the compounds reported exhibited a good pharmacokinetic (PK) profile and produced anxiolytic-like effects in the gerbil foot tapping (GFT) in vivo model.

Evidence that the metabotropic glutamate receptor 5 antagonist MPEP may act as an inhibitor of the norepinephrine transporter in vitro and in vivo.

The mechanisms through which blockade of metabotropic glutamate receptors 5 (mGluR5) results in anxiolytic and antidepressant effects are currently unknown. In the present study, we therefore hypothesized that the anxiolytic- and antidepressant-like profile of the noncompetitive mGluR5 receptor antagonist 2-ethyl-6-(phenylethynyl)-pyridine (MPEP) may be mediated by inhibition of the norepinephrine transporter (NET). Accordingly, we first examined the potency of MPEP to bind to or inhibit uptake at the NET as well as the dopamine and serotonin transporters (DAT and SERT, respectively).