Marcia E. Christy

Beta 1-selective adrenoceptor antagonists: examples of the 2-[4-[3-(substituted-amino)-2-hydroxypropoxy]phenyl]imidazole class.

A series of 2-[4-[3-(substituted-amino)-2-hydroxypropoxy]phenyl]imidazoles is described. The compounds were investigated in vitro for beta-adrenoceptor antagonism, and several examples were found to be selective for the beta 1-adrenoceptor. The structure--activity relationship exhibited by this series of compounds is discussed. (S)-2-[p-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy]phenyl]-4-(2 -thienyl)imidazole [(S)-13] was over 100 times more selective than atenolol for the beta 1-adrenergic receptor and has been selected for in-depth studies.

N-trimethylsilylpyrroles as dienes in the synthesis of 1,4-dihydronaphthalen-1,4-imines and isoindoles†

A convenient, general synthetic method for 1,4-dihydronaphthaIen-1,4-imines via the Diels-Alder addition of benzyne to N-trimethylsilylpyrrole is described. The N-trimethylsilyl protecting group protected the product from secondary benzyne reactions and was easily removed. The use of a 1,3-dipolar reagent to convert 1,4-dihydronaphthalen-1,4-imines to isoindoles via a retro-Diels-Alder sequence is illustrated.

Hyperactivity versus explosive motor behavior induced by opioids in the rat. Mechanisms elucidated with enkephalin-tyrosine-o-sulfate and morphine congeners

A relatively mild hyperactive state (HAS), characterized by agitation and hypermotility, is induced by opiate drugs and opioid peptides in general and is blocked by naloxone. HAS can be distinguished from the profound hyperresponsiveness of an explosive motor behavior (EMB). Sulfation of the phenolic moiety in morphine or in methionine enkephalin essentially abolishes opiate receptor binding activity. The sulfated peptide lacks detectable pharmacological activity in the rat, whereas sulfated morphine is several hundred-fold more potent than morphine in eliciting (EMB). Thus, EMB is elicited only by congeners of morphine having appropriate hydrophilic substitution at C-6 and which is mediated through a receptor that is insensitive to naloxone.