Synthesis of stable isotope labeled D9 -Mabuterol, D9 -Bambuterol, and D9 -Cimbuterol.

Three stable and simple synthetic routes of labeled D9 -Mabuterol, D9 -Bambuterol, and D9 -Cimbuterol were described with 98.5%, 99.7%, and 98.4% isotopic abundance and good purity. These structures and isotope-abundance were confirmed according to 1 H NMR and liquid chromatography-tandem mass spectrometry.

Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating arylsulfonamide groups.

A series of saligenin alkoxyalkylphenylsulfonamide beta(2) adrenoceptor agonists were prepared by reacting a protected saligenin oxazolidinone with alkynyloxyalkyl bromides, followed by Sonogashira reaction, hydrogenation, and deprotection. The meta-substituted primary sulfonamide was more potent than the para- and the ortho-analogues. Primary sulfonamides were more potent than the secondary and tertiary analogues. The onset and duration of action in vitro of selected compounds was assessed on isolated superfused guinea pig trachea. Sulfonamide 29b had the best profile of potency, selectivity, onset, and duration of action on both guinea pig trachea and human bronchus. Furthermore, 29b was found to have low oral bioavailability in rat and dog and also to have long duration of action in an in vivo model of bronchodilation. Crystalline salts of 29b were identified that had suitable properties for inhaled administration. A proposed binding mode for 29b to the beta(2)-receptor is presented.

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).

Importance of the aromatic ring in adrenergic amines. 6. Nonaromatic analogues of phenylethanolamine as inhibitors of phenylethanolamine N-methyltransferase: role of pi-electronic and steric interactions.

To probe the importance of pi-electronic and steric interactions of nonaromatic analogues of phenylethanolamine as inhibitors of phenylethanolamine N-methyltransferase (PNMT), a series of norbornane and norbornene ethanolamines was prepared and evaluated as inhibitors of PNMT (liquid chromatographic-electrochemical detector assay). Previous studies indicated a major importance of hydrophobic interaction of the ring moiety attached to the ethanolamine side chain, but a possible importance of pi-complex formation could have been obscured by conformational differences among the analogues. In this study, norbornane and norbornene substituted with an ethanolamine side chain at positions 1,2-exo, and 2-endo were prepared from the corresponding aldehydes by addition of trimethylsilyl cyanide (Me3SiCN) and lithium aluminum hydride reduction. The saturated (norbornane) analogues were two times more potent as inhibitors of the enzyme than were the norbornene analogues, thus suggesting that pi-complex formation is not an important contribution to binding and, as previously proposed, a hydrophobic interaction is the significant binding interaction of the ring moiety. The hydrophobic binding area has a critical size that requires the hydrophobic moiety to be of sufficient length (the bridgehead-substituted norbornane and norbornene ethanolamines being too "'short" for optimal binding). The 2-exo orientation of the ethanolamine side chain was preferred to the 2-endo orientation, supporting our earlier hypothesis that the ring moiety prefers to be oriented away from the side chain.