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In view of recent pharmacological studies suggesting the existence of δ−κ opioid receptor heterodimers/oligomers in the spinal cord, we have synthesized and evaluated (intrathecally in mice) a series of bivalent ligands (KDN series) containing κ and δ antagonist pharmacophores. Pharmacological and binding data have provided evidence for the bridging of spinal δ−κ receptor heterodimers by KDN-21 and for their identification as δ1 and κ2. The selectivity profile of KDN-21 and the apparent absence of coupled δ1−κ2 phenotypes in the brain suggest a new approach for targeting receptors.

The importance of the indole scaffold of GNTI 3 in directing its address (5'-guanidinium group) to associate with the Glu297 residue of the kappa-opioid receptor was investigated by the synthesis and biological evaluation of its 4'- (4a), 6'- (4b), and 7'- (4c) regioisomers. The finding that only the 5'-regioisomer (GNTI) possessed potent kappa-opioid antagonist activity and high affinity at kappa-receptors illustrates the importance of the 5'-position in orienting the guanidinium group to the proper recognition locus (Glu 297) for potent kappa-antagonist activity. The discovery that the 6'-regioisomer of GNTI was a potent kappa-agonist, together with the results of site-directed mutagenesis studies that are consistent with association between the 6'-guanidinium group and Glu297, suggest that the transition from an inactive to an active state of the kappa-receptor involves a conformational change of TM6. We propose that association of the 6'-guanidinium group of 4b with Glu297 promotes axial rotational motion of transmembrane helix VI which leads to receptor activation via a conformational change of inner loop 3.

Calix[4]arenes carrying H, tert-butyl, and cyanomethyl groups in the p-positions are converted into tetraesters by aroylation or acylation in the presence of 1-methylimidazole or sodium hydride. Aroylation or acylation of p-cyanomethylcalix[4]arene in the presence of aluminum chloride yield the 1,3-diesters which, upon further aroylation or acylation, provide a variety of tetraesters of mixed functionality

There has been much speculation regarding the functional relevance of G protein-coupled receptor heterodimers, primarily because demonstrating their existence in vivo has proven to be a considerable challenge. Here we show that the opioid agonist ligand 6′-guanidinonaltrindole (6′-GNTI) has the unique property of selectively activating only opioid receptor heterodimers but not homomers. Importantly, 6′-GNTI is an analgesic, thereby demonstrating that opioid receptor heterodimers are indeed functionally relevant in vivo . However, 6′-GNTI induces analgesia only when it is administered in the spinal cord but not in the brain, suggesting that the organization of heterodimers is tissue-specific. This study demonstrates a proof of concept for tissue-selective drug targeting based on G protein-coupled receptor heterodimerization. Importantly, targeting opioid heterodimers could provide an approach toward the design of analgesic drugs with reduced side effects.

Raman spectroscopic investigations on crystalline, molten and glassy ferric chloride hexahydrate (FCHH) and ferric chloride hexadeutrate (FCHD) have shown that different types of species exist in the three states. In crystalline FCHH, the results are in agreement with an earlier X-ray diffraction investigation which indicated the presence of Fe(H2O)4Cl+2 ions. In the case of crystalline FCHD, except for the alteration in the intensities of three bands, the spectrum shows features similar to those observed in the spectrum of crystalline FCHH. It has been proposed that crystalline FCHD is isomorphous with crystalline FCHH, though some expansion of the lattice is probable. In molten FCHH and FCHD Raman evidence supports the presence of tetrahedral FeCl−4 ions as the most prominent species together with a rather small concentration of trans Fe(H2O)4Cl+2 ion and Fe(D2O)4Cl+2 ion in the respective melts. The Raman spectra of glassy FCHH and FCHD have also been presented. The analyses of these spectra indicate that in the glassy FCHH and FCHD, FeCl−4 ions undergo association to form a polymeric species in which Fe3+ ions are present in octahedral coordination. The probable structure of the polymeric species is proposed.

A Raman investigation on crystalline ferric nitrate enneahydrate (FNEH) has shown that NO3− and Fe(H2O)63+ ions are present in two distinct environments in the monoclinic unit cell of the crystal. In FNEH melt, it has been found that NO3− and Fe3+ ions form a complex in which water is also coordinated to the Fe3+ ion. Raman evidence is presented which indicates that NO3− ion in the nitrate complex is coordinated to the Fe3+ ion in monodentate fashion, with an appreciable covalency in the Fe3+–ONO2− bond. The addition of water to FNEH melt causes dissociation of the nitrate complex. This complex almost ceases to exist when the water content of the melt is raised to 28 mole of water per mole of the salt. A weak polarized band at ∼407 cm−1 in the Fe(NO3)3 · xH2O system (x ≥ 28) has been attributed to the presence of the hydrolysis product of Fe3+ ions. The effect of dilution and of temperature on this band has also been investigated. It is suggested that the hydrolysis product of the salt exists in the form ...

A Raman study of ferric chloride hexadydrate (FCHH) in 11.5M HCl solutions has shown the presence of tetrahedral FeCl4− ion as the most prominent species. An appreciable concentration of a polymeric species, which is composed of higher chloroferrate groups of the type FeCl5 · H2O, and a small concentration of lower chloro‐aquoferrate complex ion of the type Fe(H2O)4Cl2+ are also present in the solutions. The saturation of FCHH‐11.5M HCl solution with dry HCl is observed to convert both the polymeric species and the lower chloro‐aquoferrate ions into FeCl4− ions. In hydrated ferric chloride melts the most prominent species exists in the form of tetrahedral FeCl4− ion along with an appreciable concentration of Fe(H2O)4Cl2+ ion. Hydrated ferric chloride melts saturated with LiCl or dry HCl gas, contains only FeCl4− ions. In the case of moderately acidic (≤ 6M HCl) ferric chloride solutions Raman evidence has revealed the presence of a polymeric species along with significant concentrations of lower chloro‐aq...