Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects.

Positive allosteric modulators (PAMs) of the mu-opioid receptor (MOR) have been hypothesized as potentially safer analgesics than traditional opioid drugs. This is based on the idea that PAMs will promote the action of endogenous opioid peptides while preserving their temporal and spatial release patterns and so have an improved therapeutic index. However, this hypothesis has never been tested.

Discovery and SAR of aryl hydroxy pyrimidinones as potent small molecule agonists of the GPCR APJ.

This article describes the discovery of aryl hydroxy pyrimidinones and the medicinal chemistry efforts to optimize this chemotype for potent APJ agonism. APJ is a G-protein coupled receptor whose natural agonist peptide, apelin, displays hemodynamic improvement in the cardiac function of heart failure patients. A high throughput screen was undertaken to identify small molecule hits that could be optimized to mimic the apelin in vitro response.

2,6-Bis(benzimidazol-2-yl)pyridine complexes of group 14 elements.

Treatment of MCl (M = Ge or Sn) with 2,6-bis(benzimidazol-2-yl)pyridine (G-BZIMPY, G = NBn, N(3,5-CF)Bn, NAllyl and O) yielded the self-ionization products [G-BZIMPYMCl][MCl] (1-6) in high yields (75-98%). Reduction reactions are examined and the nickel complexes 8 and 9 ([(NBn-BZIMPY)Ni][MCl]) are isolated from the reaction of Ni(COD) with 1 and 2 respectively. [NBn-BZIMPYSnCl][SnCl] shows a significantly stronger MLCT band in the UV-vis absorption spectrum than its germanium counterparts, with germanium complexes exhibiting negative solvatochromism that is not observed in tin complexes.

Halogen and Sulfur Oxidation of Germanium and Tin Dications.

Herein we present the oxidation of base-stabilized tetrel dications [LM][OTf] [L = BIMEt = tris(1-ethyl-benzoimidazol-2-ylmethyl)amine and M = Ge, Sn] with PCl, SeCl, Br, and I to access dicationic dihalides [LMX][OTf]. The addition of oxygen-rich donor molecules (picoline N-oxide, OPEt) to dications [LM][OTf] yielded donor-acceptor complexes bearing a tetrel(II) dication adjacent to a pnictogen(V) moiety. The addition of elemental sulfur to [LGe][OTf] yielded [(LGeS)][OTf] containing a dimeric tetracation.

Identification and biochemical analyses of selective CB agonists.

Cannabinoid CB and CB receptors are activated by Δ-tetrahydrocannabinol, a psychoactive component of marijuana. The cannabinoid CB receptor is primarily located in the brain and is responsible for the psychoactive side effects, whereas the cannabinoid CB receptor is located in immune cells and is an attractive target for immune-related maladies. We identify small molecules that selectively bind to the cannabinoid CB receptor and can be further developed into therapeutics.

2,6-Bis(benzimidazol-2-yl)pyridines as more electron-rich and sterically accessible alternatives to 2,6-bis(imino)pyridine for group 13 coordination chemistry.

Treatment of GaCl3 with 2,6-bis(benzimidazol-2-yl)pyridine (G-BZIMPY, G = NBz, N(3,5-CF3)Bz, N-allyl and O) yielded the autoionization products [G-BZIMPYGaCl2][GaCl4] (1-4) in great yields. The Ga(iii) complex 1 was reduced to Ga(i) using K2[Fe(CO)4], resulting in the complex [(NBzBZIMPY)(Cl)Ga-Fe(CO)4] (7). GaCl3 and AlCl3 were complexed by the structurally similar bis(imino)pyridine (DIMPY) and the resulting complexes are compared to those of G-BZIMPY.

Synthesis, characterization and mass-spectrometric analysis of [LSn(IV)F] salts [L = tris ((1-ethyl-benzoimidazol-2-yl)methyl)amine, x = 1-4].

A series of complexes with the formulae [(BIMEt3)SnF4-x][OTf]x with x = 1-4 has been synthesized by successive fluoride abstraction from SnF4 with TMSOTf in the presence of the tetradentate nitrogen donor BIMEt3 (tris ((1-ethyl-benzoimidazol-2-yl)methyl)amine). Single crystal X-ray diffraction and heteronuclear NMR spectroscopic analysis provided insight into these new main group cations. Electrospray ionization mass spectrometric analysis on solutions containing the different salts allowed for successful detection of the cations [(BIMEt3)SnF]3+, [(BIMEt3)SnF2]2+ and [(BIMEt3)SnF3]+.

Tris(benzoimidazol)amine (L) complexes of pnictogen(iii) and pnictogen(v) cations and assessment of the [LP]/[LPF] redox couple.

A series of cationic complexes involving a pnictogen(iii) (Pn = P, As, Sb) centre and the tetradentate ligand tris((1-ethyl-benzoimidazol-2-yl)methyl)amine (BIMEt) have been synthesized and comprehensively characterized. Oxidation of [P(BIMEt)] with XeF provides access to [PF(BIMEt)] representing the first structurally characterized example of a phosphorus(v) centred trication.

Oxidation of a germanium(ii) dication to access cationic germanium(iv) fluorides.

The synthesis and characterization of the tris(1-ethyl-benzoimidazol-2-ylmethyl)amine (BIMEt3 = L) complex of Ge(ii)2+ is described. Oxidation of [LGe]2+ with Selectfluor gives [LGeF2]2+, in a process that is envisaged to involve a tricationic complex [LGeF]3+ as an intermediate, which has been isolated by fluoride ion abstraction from [LGeF2]2+.

Tris(1-methyl-imidazol-2-yl)phosphane Complexes of Pnictogen, Tetrel, and Triel Cations.

cations gallium indium nitrogen ligands pnictogens tetrelThe synthesis and characterization of salts with the generic formula [P(Im) M][OTf] (Im=1-methyl-imidazol-2-yl; M=P, As or Sb and x=3; M=Ge or Sn and x=2) are reported. In all cases, the cations adopt a cage structure with two chemically and energetically distinct apical lone pairs. In contrast, complexes of gallium and indium engage two P(Im) ligands resulting in a distorted octahedral geometry for the triel center in compounds of the generic formula [{P(Im) } M][OTf] (M=Ga or In).

Complexes of Stiboranium Mono-, Di-, and Trications.

Reaction of Ph SbCl with 2,2'-bipyridine and Me SiOSO CF releases chlorobenzene, which is interpreted as a reductive (Sb /Sb ) elimination from a complex of a stiboranium cation. Conversely, reactions of Ph SbCl with 4-methylpyridine-N-oxide and AgOSO CF give redox-resistant complexes with the generic formulae [Ph SbCl L ][OTf] , including a compound containing a pnictogen(V) trication.

Discovery of Selective Cannabinoid CB Receptor Agonists by High-Throughput Screening.

The endocannabinoid system (ECS) plays a diverse role in human physiology ranging from the regulation of mood and appetite to immune modulation and the response to pain. Drug development that targets the cannabinoid receptors (CB and CB) has been explored; however, success in the clinic has been limited by the psychoactive side effects associated with modulation of the neuronally expressed CB that are enriched in the CNS. CB, however, are expressed in peripheral tissues, primarily in immune cells, and thus development of CB-selective drugs holds the potential to modulate pain among other indications without eliciting anxiety and other undesirable side effects associated with CB activation.

Pharmacologic Evidence for a Putative Conserved Allosteric Site on Opioid Receptors.

Allosteric modulators of G protein-coupled receptors, including opioid receptors, have been proposed as possible therapeutic agents with enhanced selectivity. BMS-986122 is a positive allosteric modulator (PAM) of the -opioid receptor (-OR). BMS-986187 is a structurally distinct PAM for the -opioid receptor (-OR) that has been reported to exhibit 100-fold selectivity in promoting -OR over -OR agonism.

Standard Curves Are Necessary to Determine Pharmacological Properties for Ligands in Functional Assays Using Competition Binding Technologies.

Homogeneous functional assays that utilize competition binding technology are widely used for determining pharmacological properties such as intrinsic activity and potency. One example is time-resolved fluorescence resonance energy transfer (TR-FRET) 3',5'-cyclic adenosine monophosphate (cAMP) assays, where labeled cAMP (tracer) and a labeled anti-cAMP antibody bind together to produce a TR-FRET signal when the two constituents are proximal to each other. This signal is disrupted when unlabeled and cellularly generated cAMP competes with the tracer cAMP for binding to the labeled antibody.

Hypothalamic-Pituitary-Adrenal Axis Modulation of Glucocorticoids in the Cardiovascular System.

The collective of endocrine organs acting in homeostatic regulation-known as the hypothalamic-pituitary-adrenal (HPA) axis-comprises an integration of the central nervous system as well as peripheral tissues. These organs respond to imminent or perceived threats that elicit a stress response, primarily culminating in the release of glucocorticoids into the systemic circulation by the adrenal glands. Although the secretion of glucocorticoids serves to protect and maintain homeostasis in the typical operation at baseline levels, inadequate regulation can lead to physiologic and psychologic pathologies.

Substitution Reactions at BIAN Supported Fluoroantimony Cations Yielding Cyanoantimony and Azidoantimony Cations.

This work presents new cationic coordination complexes of antimony with the 1,2-bis[(2,6-diisopropylphenyl)imino]acenaphthene ( BIAN) ligand system. The fluoroantimony complexes [SbF( BIAN)][OTf] and [SbF ( BIAN)][OTf] have been successfully isolated and characterized. The fluorine substituent in the Lewis acidic complex [SbF( BIAN)][OTf] can be selectively replaced without degradation of the Sb- BIAN interaction to give the first dicationic azido and cyano derivatives, [Sb(CN)( BIAN)][OTf] and [Sb(N )( BIAN)][OTf] , which have been isolated and structurally characterized.

Reversible Oxidative Se-Se Coupling of Phosphine Selenides by Ph Sb(OTf).

Salts of diphosphoniumdiselenide dications ([R PSeSePR ][OTf] ) have been isolated from reactions of trialkylphosphine selenides with triphenylantimony bistriflate. The redox process is speculated to proceed via a cationic coordination complex [Ph SbL ][OTf] (L=Me PSe, iPr PSe), which is also formed in the reaction of [R PSeSePR ][OTf] with Ph Sb. The observations indicate that the reductive elimination of [R PSeSePR ] from [Ph Sb(SePR ) ] is reversible through the oxidative addition of [R PSeSePR ] to Ph Sb.

Cationic 2,2'-bipyridine complexes of germanium(ii) and tin(ii).

We present the first systematic study of 2,2'-bipyridine complexes of E(ii) cationic acceptors (E = Ge, Sn). The complexes were comprehensively characterized by spectroscopic and crystallographic methods to yield complexes of ECl and E. Computational DFT methods were also employed to survey the bonding in the cations, along with an examination of their molecular orbitals (MOs).

Tris(2-pyridyl)phosphine as a versatile ligand for pnictogen acceptors.

We report cationic complexes of arsenic and antimony with the tris(2-pyridyl)phosphine ligand. Chloride ion abstraction from AsCl using TMSOTf in the presence of the ligand gives [P(Pyr)As][OTf], in which the trication adopts a C symmetric cage structure. The reaction proceeds via the intermediate [P(Pyr)AsCl][OTf], which undergoes chloride exchange to give [P(Pyr)As][OTf] and [P(Pyr)AsCl][OTf].

Endogenous opioids regulate moment-to-moment neuronal communication and excitability.

Fear and emotional learning are modulated by endogenous opioids but the cellular basis for this is unknown. The intercalated cells (ITCs) gate amygdala output and thus regulate the fear response. Here we find endogenous opioids are released by synaptic stimulation to act via two distinct mechanisms within the main ITC cluster.

Bond fission in monocationic frameworks: diverse fragmentation pathways for phosphinophosphonium cations.

A series of phosphinophosphonium cations ([RPPMe]; R = Me, Et, Pr, Bu, Cy, Ph and N Pr) have been prepared and examined by collision-induced dissociation (CID) to determine the fragmentation pathways accessible to these prototypical -phosphorus cations in the gas-phase. Experimental evidence for fission of P-P and P-E (E = P, C) bonds, and β-hydride elimination has been obtained. Comparison of appearance potentials for the P-P bond dissociation fragments [RP] (P-P heterolysis) and [PMe]˙ (P-P homolysis) shows that heterolytic P-P cleavage is more sensitive than P-P homolysis towards changes in substitution at the trivalent phosphorus center.

Condensation Reactions of Chlorophosphanes with Chalcogenides.

A high-yielding and facile synthesis for diphosphane monochalcogenides (1(Ch)((R))) and their constitutional isomers, diphosphanylchalcoganes (2(Ch)((R))), was developed, featuring a condensation reaction between chlorophosphanes (R2PCl) and sodium chalcogenides (Na2Ch, Ch = S, Se, (Te)). The optimized protocol selectively yields either 1(Ch)((R)) (R2(Ch)PPR2) or 2(Ch)((R)) (Ch(PR2)2) depending upon the steric demand of the substituents R. Reaction pathways consistent with the distinct reaction outcomes are proposed.

Correction: Bipyridine complexes of E (E = P, As, Sb, Bi): strong Lewis acids, sources of E(OTf) and synthons for E and E cations.

[This corrects the article DOI: 10.1039/C5SC02423D.].

Distinction between coordination and phosphine ligand oxidation: interactions of di- and triphosphines with Pn(3+) (Pn = P, As, Sb, Bi).

Reactions of polydentate phosphines with sources of Pn(3+) (Pn = P, As, Sb, Bi) yield complexes of Pn(1+) (Pn = P, As) or Pn(3+) (Pn = Sb, Bi) acceptors. The distinction between coordination of a phosphine center to Pn and oxidation of a phosphine ligand is dependent on Pn. The first structurally verified triphosphine complexes of Sb(III) and Bi(III) acceptors are reported.