No abstract

A series of unsubstituted and methoxy-substituted 2-amidotetralins (4a-q) was prepared and evaluated for their ability to compete for 2-[125I]iodomelatonin binding to chicken retinal membranes and for their potency to inhibit the calcium-dependent release of [3H]dopamine from rabbit retina. The lead compound, 2-acetamido-8-methoxytetralin (4j), showed a moderate affinity (Ki = 46 nM) and potency (IC50 = 1.4 nM) at the melatonin receptor. The structural requirements necessary for optimal agonistic activity at the melatonin receptor are as follows. First, the amido group, which should have a small, nonbranched alkyl group, is essential for affinity, and second, the methoxy substituent at the 8-position of the 2-amidotetralin ring is essential for optimal agonistic activity at the melatonin receptor. We concluded that this series of unsubstituted and methoxy-substituted 2-amidotetralins constitutes a class of nonindolic melatonin-like agents that can be used as pharmacological tools to further characterize melatonin receptors and to elucidate the mode of action of melatonin.

High concentrations of dopamine were found in the nucleus accumbens and olfactory tubercle of the rat brain using a radiochemical enzymatic assay technique. An active uptake system for [3H]dopamine that is temperature sensitive and dependent on external sodium ions is present in synaptosome-rich homogenates of these two brain areas. This uptake process is potently inhibited by benztropine (ICso = 2.0 x lo-' M). Dextroamphetamine d was 4.5 times more potent than 1-amphetamine in inhibiting dopamine uptake in the nucleus accumbens and six times more potent in the olfactory tubercle and corpus striatum. Low concentrations of dopamine caused an increase in adenosine 3'5'-monophosphate (cyclic AMP) formation in homogenates of both the nucleus accembens and olfactory tubercle. This effect was potently blocked by chlorpromazine. The a-adrenoceptor antagonist phentolamine weakly antagonized the stimulation of this adenylate cyclase by dopamine, but the B-adrenoceptor antagonist propranolol did not. N r u m 22/2--~

Summary1. The effects of various phenylethylamine analogues on the inhibition of 3H-noradrenaline and 3H-dopamine uptake into homogenates of rat hypothalamus and corpus striatum respectively, were examined. 2. Phenolic hydroxyl groups and a-methylation of the side chain were both found to enhance the affinity for the neuronal uptake sites.3. Methoxylation, ,8-hydroxylation and N-methylation were all found to reduce the ability of a compound to inhibit catecholamine transport. 4. The noradrenaline and dopamine transport systems responded in a quantitatively different manner to the various phenylethylamine analogues. It was found that, in general, the noradrenaline uptake process was more sensitive to structural changes, both positive and negative, than the dopamine system.

Phenothiazines and butyrophenones are known to alter dopamine (3,4-dihydroxyphenethylamine) metabolism in the brain in a fashion suggesting that they may block dopamine receptors. We observed, using Dreiding molecular models, that dopamine in its solid-state conformation is superimposable upon a portion of the known x-ray structure of chlorpromazine 12-chloro-10-(3-dimethylaminopropyl)-phenothiazine]. The ability of phenothiazine drugs to mimic the dopamine-like conformation correlates with their antischizophrenic efficacy. These structure-activity relationships explain the importance of a substituent in ring a, a three-carbon side chain bearing the amino group, and a hetero atom between rings a and c.

No abstract

A simple, efficient, economic, and sensitive method is presented for the detection of choline and acetylcholine in neuronal tissue using HPLC, a postcolumn enzyme reactor with immobilized enzyme, and electrochemical detection. The method is based on a separation of choline and acetylcholine by cation exchange HPLC followed by passage of the effluent through a postcolumn reactor containing a mixture of acetylcholinesterase and choline oxidase; the latter enzyme converts choline to betaine and hydrogen peroxide, the former enzyme hydrolyzes acetylcholine to acetate and choline. The hydrogen peroxide produced is electrochemically detected. A simple and efficient preparation of neuronal tissue is described using an optional prepurification step on Sephadex G-10 columns, offering the possibility to detect choline and acetylcholine as well as catecholamines and their related metabolites in the same tissue sample. The sensitivity of the assay system is 250 fmol for choline and 500 fmol for acetylcholine.

No abstract