Bis-catechol-substituted redox-reactive analogues of hexamethonium and decamethonium: stimulated affinity-dependent reactivity through iron peroxide catalysis.

Symmetrically bis-catechol-substituted analogues (1 and 2, respectively) of hexamethonium and decamethonium were synthesized and investigated as redox-activated affinity reagents toward the neurotoxin-binding sites of the nicotinic acetylcholine receptor (nAcChR), purified from Torpedo californica electroplax. These reagents bound to nAcChR with Kd = 1.8 x 10(-8) and 2.3 x 10(-7) M for 1 and 2, respectively. In the presence of a metal, Fe(II)/Fe(III), and peroxide, both reagents produced a rapid and efficient half-of-sites inactivation of neurotoxin-binding sites in the nAcChR in a concentration-dependent manner, which paralleled the extent of receptor binding of the reagents. In the absence of Fe(II)/Fe(III) peroxide, redox-dependent inactivation occurred for both 1 and 2 more slowly and only at concentrations much higher (10(3)-10(4) times) than those necessary to produce significant binding to nAcChR. However, receptor inactivation in the absence of added metal peroxide was still more efficient for 1 and 2 than observed previously for [(trimethylammonio)methyl]catechol (3), the prototypic redox-dependent affinity reagent after which 1 and 2 were patterned. Thus, the new reagents reported are expected to provide more efficient and selective conditions for redox-dependent inactivation at nAcChR and other macromolecular sites to which such reagents may be directed.

Potential organ- or tumor-imaging agents. 18. Radioiodinated diamines and bisquaternaries.

The purpose of this research was to employ diamines and their quaternary derivatives as carrier molecules for gamma-emitting radiation. The diamine putrescine is widespread in nature and has been reported to selectively concentrate in the rat ventral prostate and pancreas. This study confirms the selective uptake of radioactivity in the rat ventral prostate, but not in the pancreas, following administration of [14C]putrescine. The radioiodinated analogues of putrescine showed no predilection for either of these organs. On the other hand, radioactivity associated with a radioidinated quaternary derivative (3) was found to accumulate incartilaginous tissues such as trachea, intervertebral disks, and chondrosarcoma tumor in a manner simular to hexamethonium.

Synthesis and biological activity of spin-labeled analogs of biotin, hexamethonium, decamethonium, dichlorisoproterenol, and propranolol.

Spin-labeled analogs of biotin (vitamin H), hexamethonium, decamethonium, dichlorisoproterenol, propranolol, and primaquine containing the nitroxide free radical have been synthesized and tested for biological activity. The four spin-labeled analogs of biotin, 4-biotinamido-2,2,6,6-tetramethyl-1-piperidinyloxy (IV), 3-biotinamido-2,2,5,5-tetramethyl-1-pyrrolidinyloxy (V), 3-biotinamidomethyl-2,2,5,5-tetramethyl-1-pyrrolidinyloxy (VI), and 4-(biotinylglycyl)amino-2,2,6,6-tetramethyl-1-piperidinyloxy (VII), all interacted with avidin, a specific biotin binding protein found in raw egg white, at the same sites as did biotin itself. An unsymmetrical decamethonium spin label (XVIII) in which one of the quaternary methyl groups had been replaced by the 4-(2,2,6,6-tetramethyl-1-piperidinyloxy) moiety was 13 times more potent as an inhibitor of Torpedo californica acetylcholinesterase than the parent drug. The symmetrical decamethonium (XVI) and hexamethonium (XIV) spin labels were 18 and 1.8 times as active as decamethonium in the same assay system. The substitution of the 4-(2,2,6,6-tetramethyl-1-piperidinyloxy) group for the isopropyl groups of beta-adrenergic blocking drugs dichlorisoproterenol and propranolol, to give spin labels XXI and XXII, caused a 45 and 54% reduction, respectively, in the ability of these compounds to inhibit the isoproterenol-stimulated activity of rat fat cell membranes. Finally, modification of primaquine by the introduction of the 4-(2,2,6,6-tetramethyl-1-piperidinyloxy) substituent into the amino group of the butyl side chain completely abolished the ability of the drug to bind to nuclei acids. These results suggest that the incorporation of the nitroxide group into drug molecules may be a useful approach to the synthesis of more specific spin labels for biological systems, such as egg white avidin, acetylcholinesterase, and the beta-adrenergic receptor.