Synthesis and structure-activity relationships and effects of phenylpropanoid amides of octopamine and dopamine on tyrosinase inhibition and antioxidation.

Phenylpropanoid amides of octopamine (OA) 1a-1e and dopamine (DA) 2a-2e were synthesised and the structure-activity relationships (SARs) for antioxidant and tyrosinase inhibition activities were analysed. Among synthesised compounds, 2c, which contains two catechol moieties, exhibited the most DPPH radical-scavenging activity (EC(50)=16.2 ± 2.4 µM), and 1d exhibited significant tyrosinase inhibitory activity (IC(50)=5.3 ± 1.8 µM). Interestingly, with the same acid moiety, OA derivatives showed more inhibitory effect on tyrosinase than did compounds derived from DA, whereas DA derivatives were found to have higher antioxidant activity than compounds derived from OA. The relationship between their structures and their potencies, demonstrated in the current study, will be useful for the design of optimal agents.

Coumarin-based octopamine phototriggers and their effects on an insect octopamine receptor.

We have developed and characterized efficient caged compounds of the neurotransmitter octopamine. For derivatization, we introduced [6-bromo-8-(diethylaminomethyl)-7-hydroxycoumarin-4-yl]methoxycarbonyl (DBHCMOC) and {6-bromo-7-hydroxy-8-[(piperazin-1-yl)methyl]coumarin-4-yl}methoxycarbonyl (PBHCMOC) moieties as novel photo-removable protecting groups. The caged compounds were functionally inactive when applied to heterologously expressed octopamine receptors (AmOctα1R). Upon irradiation with UV-visible or IR light, bioactive octopamine was released and evoked Ca2+ signals in AmOctα1R-expressing cells. The pronounced water solubility of compounds 2-4 in particular holds great promise for these substances as excellent phototriggers of this important neurotransmitter.

Radiolabeled phenethylguanidines: novel imaging agents for cardiac sympathetic neurons and adrenergic tumors.

The norepinephrine transporter (NET) substrates [123I]-m-iodobenzylguanidine (MIBG) and [11C]-m-hydroxyephedrine (HED) are used as markers of cardiac sympathetic neurons and adrenergic tumors (pheochromocytoma, neuroblastoma). However, their rapid NET transport rates limit their ability to provide accurate measurements of cardiac nerve density. [11C]Phenethylguanidine ([11C]1a) and 12 analogues ([11C]1b-m) were synthesized and evaluated as radiotracers with improved kinetics for quantifying cardiac nerve density. In isolated rat hearts, neuronal uptake rates of [11C]1a-m ranged from 0.24 to 1.96 mL min-1 (g wet wt)-1, and six compounds had extremely long neuronal retention times (clearance T1/2 > 20 h) due to efficient vesicular storage. Positron emission tomography (PET) studies in nonhuman primates with [11C]1e, N-[11C]guanyl-m-octopamine, which has a slow NET transport rate, showed improved myocardial kinetics compared to HED. Compound [11C]1c, [11C]-p-hydroxyphenethylguanidine, which has a rapid NET transport rate, avidly accumulated into rat pheochromocytoma xenograft tumors in mice. These encouraging findings demonstrate that radiolabeled phenethylguanidines deserve further investigation as radiotracers of cardiac sympathetic innervation and adrenergic tumors.

A new copper(I)-tetrahydrosalen-catalyzed asymmetric Henry reaction and its extension to the synthesis of (S)-norphenylephrine.

A new chiral hydrogenated salen catalyst has been developed for the asymmetric Henry reaction which produces the expected products in moderate to high yields (up to 98 %) with excellent enantioselectivities (up to 96 % ee). A variety of aromatic, heteroaromatic, enal, and aliphatic aldehydes were found to be suitable substrates in the presence of hydrogenated salen 1 f (10 mol %), (CuOTf)(2)C(7)H(8) (5 mol %), and 4 A molecular sieves. This process is air-tolerant and easily manipulated with readily available reagents, and has been successfully extended to the synthesis of (S)-norphenylephrine in 67 % overall yield, starting from commercially available m-hydroxybenzaldehyde. Based on experimental investigations and MM+ calculations, a possible catalytic cycle including a transition state (8 or A) has been proposed to explain the origin of reactivity and asymmetric inductivity.

Aromatic N-hydroxyguanidines as new reduction cosubstrates for dopamine beta-hydroxylase.

Conversion of neurotransmitter dopamine into norepinephrine is catalyzed by dopamine beta-hydroxylase (DbH). The reaction requires the presence of both molecular oxygen and a reducing cosubstrate, the assumed physiological cosubstrate being ascorbic acid. We have investigated the ability of a new family of molecules, N-aryl-N'-hydroxyguanidines, to serve as cosubstrates for DbH. N-(4-Methoxyphenyl)-N'-hydroxyguanidine proved to be an efficient reducing agent for DbH. The complete N-hydroxyguanidine moiety was required for activity, as any modification of this function resulted in non-cosubstrate compounds. Moreover, analysis of the products formed from N-(4-methoxyphenyl)-N'-hydroxyguanidine showed that the main oxidation product was a nitrosoimine. Modification of the aromatic para-substituent evidenced an influence of its electronic properties on the catalytic activity whereas steric factors seemed less important. In addition, changing the methoxy-substituent from the para- to the ortho-position led to an inactive compound. Our results demonstrate that N-aryl-N'-hydroxyguanidines are new efficient reducing cosubstrates for DbH and prove that specific interactions with the reducing cosubstrate do take place at the active site of the enzyme.

Three-dimensional molecular-field analyses of octopaminergic agonists for the cockroach neuronal octopamine receptor.

The quantitative structure-activity relationship of a set of 40 octopaminergic agonists against receptor 2 in cockroach nervous tissue, was analyzed using molecular-field analysis (MFA). MFA on the study set of those compounds evaluated effectively the energy between a probe and a molecular model at a series of points defined by a rectangular grid. Contour surfaces for the molecular fields were presented and the results provided useful information in the characterization and differentiation of octopaminergic receptor.

Selective synthesis of racemic 1-11C-labelled norepinephrine, octopamine, norphenylephrine and phenylethanolamine using [11C]nitromethane.

A new and simple method for the selective condensation of no-carrier-added [11C]nitromethane (1) with various substituted (protected) benzaldehydes to [beta-11C]beta-nitrophenethyl alcohols was developed. This method which utilizes tetrabutylammonium fluoride in THF as a catalyst gave a condensation yield of 80-90% and a selectivity of 80-90% for [11C]nitroalcohol vs [11C]nitrostyrene formation within 2 min. Reduction of these [11C]nitroalcohols with Raney nickel in formic acid gave the corresponding [11C]aminoalcohols in a yield of 60-90%. Boron tribromide was used for the cleavage of 4-methoxy and 3,4-(methylenedioxy) phenol protecting groups. After HPLC-purification, racemic 1-11C-labelled norepinephrine (7), phenylethanolamine (4), norphenylephrine (5) and octopamine (6) were prepared in a 12-30% decay corrected total radiochemical yield (20-50% counted from 1) with an overall synthesis time of 40-70 min from end of bombardment (EOB). The radiochemical purity was > 98% and the specific radioactivity 700-1500 Ci/mmol (26-56 GBq/mumol).

[11C]octopamine synthesis using [11C]cyanide: chemical and enzymatic approaches for the [11C]cyanohydrin synthesis.

[11C]-p- and m-octopamine hydrochloride were synthesized from [11C]HCN in a two-step sequence. Chemical and enzymatic approaches were used for the formation of the [11C]cyanohydrin intermediates as the key step. Isolated radiochemical yields of 0.7-2.3% at the end-of-synthesis were obtained with an overall preparation time of 40-60 min. The enantiomeric purity of the [11C]-p-octopamine obtained through the enzymatic process was 92% e.e. in the (S)-enantiomer, whereas that of the [11C]-m-octopamine was 42% e.e. in the (R)-enantiomer, as determined by HPLC without any derivatization.