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In a search for inhibitors of epinephrine biosynthesis as potential therapeutic agents, a series of 13 ring-chlorinated 1,2,3,4-tetrahydroisoquinolines was prepared. These compounds were tested initially for their ability to inhibit rabbit adrenal phenylethanolamine N-methyltransferase (PNMT) in vitro. Enzyme-inhibitor dissociation constants, determined for the six most potent members of the series, indicated the following order of decreasing potency: 7,8-Cl2 greater than 6,7,8-Cl3 greater than 7-Cl approximately 5,6,7,8-Cl4 greater than 5,7,8-Cl3. These compounds were subsequently examined for PNMT-inhibiting activity in intact rats and mice. 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline (13, SK&F 64139) was the most potent member of the series both in vitro and in vivo and is currently undergoing clinical investigation.

1,2,3,4-Tetrahydroisoquinoline-7-sulfonanilides (1-14) related to 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (21,SK&F 29661) were prepared and studied for their ability to inhibit phenylethanolamine N-methyltransferase (PNMT) in vitro. The choice of substituents on the 7-phenyl group of the sulfonanilides was based on the Topliss approach to structure-activity relationship studies. Information about the importance of an acidic hydrogen atom on the sulfonamide nitrogen atom was obtained from the preparation and testing of a tertiary N-methylsulfonanilide (15). Other THIQ's (1,2,3,4-tetrahydroisoquinolines) containing sulfur substituents in the 7 position were prepared and tested and consisted of 7-N-benzyl and 7-N-phenethyl derivatives of SK&F 29661 (16-18) and 7-(phenacylthio)-and 7-(phenacylsulfonyl)-THIQ (19 and 20). The two most potent inhibitors were the 7-p-bromo- and -chlorosulfonanilides, 2 and 6. However, neither was an effective inhibitor of norepinephrine to epinephrine conversion when tested in an in vivo mouse assay at unit doses of 25 or 100 mg/kg.

A series of substituted 2-arylthiazolo[3,2-a]pyridinium salts (1a-q) was prepared by known methods and tested for hypoglycemic activity in 48-h fasted rats. Two compounds, 2-phenylthiazolo- and 8-methyl-2-phenythiazolo[3,2-a]pyridinium perchlorate (1a and 1q), showed consistent hypoglycemic activity in this screen, demonstrating that a high degree of structural specificity was required for hypoglycemic activity. At higher doses the hypoglycemic activity of 1a and 1q was associated with elevated levels of hepatic triglycerides.

Catecholamines, such as epinephrine, inhibit the enzyme adenylate cyclase (EC 4.6.1.1) via a specific receptor mechanism involving a2-adrenergic receptors. In order to facilitate purification of these inhibitory receptors we have prepared a highly effective biospecific affinity adsorbent. The immobilized ligand SKF 101253 is a 3-benzazepine with a2-adrenergic antagonist activity. SKF 101253 is coupled to Sepharose CL-4B by using a bifunctional reagent (1,4-butanediol diglycidyl ether) which also provides a hydrophilic spacer moiety between the ligand and the gel matrix. Membranes from human platelets, containing a12-ad- To understand fully the coupling of stimulatory and inhibitory receptors to adenylate cyclase it will be important to purify these receptors. Progress in this regard has been made for the adenylate cyclase-stimulatory f3-adrenergic receptor (2); however, purification of the adenylate cyclase-inhibitory a2-adrenergic receptor has not been achieved. A formidable problem in the purification of membrane-bound receptors is their miniscule quantity relative to the complete chemical content of the cell. An additional difficulty is the need for solubilization of the receptor from the membrane. Solubilization of membranebound proteins is usually incomplete, and it may lead to receptor inactivation which exacerbates the problem of the low initial concentration of receptor. Furthermore, due to the similarity of physiochemical properties among detergent-solubilized proteins, solubilization vitiates the use of many of the traditional methods for the purification of macromolecules.Affinity chromatography, a technique that exploits the specificity and affinity of ligand-receptor interactions, can over-

Human platelets contain alpha 2-adrenoceptors which are negatively coupled to the enzyme adenylate cyclase. In order to better understand the interaction of this subtype of alpha receptor with this key enzyme, we have initiated a program to isolate and characterize the alpha 2-adrenoceptor. This report describes the synthesis and biological characterization of a series of molecules that were prepared as affinity ligands for this purpose. The best of these is 9-(allyloxy)-6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SK&F 101253). This compound is an alpha 2-adrenoceptor antagonist, which was obtained by synthetic modification of 6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SK&F 86466), a novel antagonist with high affinity for the alpha 2-receptor.

The potent hypoglycemic activity of 3-(3-methyl-2-pyridyl)propan-1-ol (1) prompted us to synthesize and study related structures. Some of the variables studied were the position of the methyl and alcohol side chains, the distance between the heterocyclic ring and the hydroxyl group, the effect of additional nuclear substitution, and the effects of branching and substitution on the alcohol side chain. The compounds were tested in 48-h fasted rats, usually at a dose of 150 mg/kg po. 1, the corresponding propionic acid 12, the acetate and methyl ether of 1 (22 and 23), and the 5-methyl analogue of 1 (29) were of comparable hypoglycemic potency. However, these compounds all caused a concomitant elevation of hepatic triglycerides and/or death in the test animals when observations were continued for 4--24 h.