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Biomedical subjects

H J Hess

Publications and source records attributed to H J Hess.

30 records · Page 2Linked to original sources
PubMed1979

Development of ethyl 3,4-dihydro-4-oxopyrimido[4,5-b]quinoline-2-carboxylate, a new prototype with oral antiallergy activity.

Structural modification of 3,4-dihydro-4-oxoquinazoline-2-carboxylic acid leading to ethyl 3,4-dihydro-4-oxopyrimido[4,5-b]quinoline-2-carboxylate, a new prototype with oral antiallergy activity of the disodium cromoglycate type, is described. This prototype is 10 times more potent than disodium cromoglycate in the rat passive cutaneous anaphylaxis test. Structure-activity studies indicate that a carboxylic acid moiety directly attached to the 2 position of the pyrimidine ring is most favorable for intravenous activity while esters of this acid are preferred for oral activity. The oral activity of ethyl 3,4-dihydro-4-oxopyrimido[4,5-b]quinoline-2-carboxylate (ED50 = 3 mg/kg) places this ester among the more potent orally active antiallergy agents reported to date.

Animals↗
PubMed1979

Synthesis and biological activity of carboxyl-terminus modified prostaglandin analogues.

A series of PGE2, 16,16-dimethyl-PGE2, and PGF2 alpha analogues modified at the carboxyl terminus with tetrazole, amide, acylurea, imide, and sulfonimide functionalities was evaluated for uterine stimulant, bronchodilator, hypotensive, gastric antisecretory, and diarrheal activity. These compounds were prepared by modification of the Corey prostaglandin synthesis utilizing as a key step condensation of known hemiacetals with the ylide derived from the requisite substituted phosphonium salts. Structure--activity relationships suggest that a proton at the C-1 position appears necessary for agonist activity and the acidity of this proton has a relatively greater influence on activity than pendant steric bulk. Noteworthy are the tissue-selective bronchodilator activity of N-acetyl-PGE2-carboxamide and the selectivity for uterine tissue of N-methanesulfonyl-PGE2-carboxamide, 2-decarboxy-2-(tetrazol-5-yl)-16,16-dimethyl-PGE2, N-acetyl-16,16-dimethyl-PGE2-carboxamide, and N-methanesulfonyl-16,16-dimethyl-PGE2-carboxamide.

Animals↗
PubMed1977

A tissue-selective prostaglandin E2 analog with potent antifertility effects.

N-methanesulfonyl 16-phenoxy-omega-tetranor PGE2 is a prostaglandin analog which is markedly more tissue selective than PGE2. This compound is 10-30 times more potent than PGE2 in animal models which are considered relevant to antifertility effects in humans. In pharmacological tests which are believed to be predictive for side effects in humans, the compound has potency either equal to or less than that of PGE2.

Abortifacient Agents↗
PubMed1977

Synthesis and identification of the major metabolites of prazosin formed in dog and rat.

The 6-O-demethyl and 7-O-demethyl analogues of the new antihypertensive drug prazosin [2-[4-(2-furoyl)-piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline hydrochloride] have been unequivocally synthesized via separate ten-step reaction sequences starting from isovanillin and vanillin, respectively. The 6-O-demethyl derivative was found to be identical with the major prazosin metabolite formed in dog and rat, while the 7-O-demethyl derivative was identical with another, less prevalent but significant metabolite. Two minor metabolites of prazosin, 2-(1-piperazinyl)-4-amino-6,7-dimethoxyquinazoline and 2,4-diamino-6,7-dimethoxyquinazoline, are also described. All four metabolites are less potent blood pressure lowering agents in dogs than prazosin but may contribute to its antihypertensive effect, since they account for a major portion of the administered dose.

Animals↗
PubMed1975

Analysis of the hypotensive action of prazosin.

Results of animal studies indicate that the hypotensive effect of prazosin is due to vasodilatation which is dependent on two discernible components of drug action: (1) direct relaxation of vascular smooth muscle and (2) interference with peripheral sympathetic function at a site distal to the alpha-adrenergic receptor.

Animals↗
PubMed1975

Prazosin: biochemistry and structure-activity studies.

Prazosin, a structurally and mechanistically novel antihypertensive agent, is the culmination of a systematic synthesis and pharmacologic developmental effort which had as its goal the development of an agent that would lower blood pressure by direct vasodilation. Pharmacologic studies have demonstrated that the vasodilator action of prazosin is confined primarily to the arterioles and that antihypertensive effects are unaccompanied by excessive increases in heart rate. Evidence is presented rationalizing these observations on a biochemical basis. Results of inhibitory studies with isolated cyclic nucleotide phosphodiesterases are consistent with the hypothesis that prazosin elicits its therapeutic effects by increasing intracellular levels of cyclic AMP at vascular sites and intracellular levels of cyclic GMP at cholinergic receptor sites in the heart. Tissue distribution studies with radioactive prazosin-2-14C are in accord with this rationale and further support the mechanistic conclusions reached on the basis of pharmacologic observations. Pharmacokinetic and biotransformation studies indicate that prazosin is well absorbed and is excreted principally in metabolized form with biliary excretion being the major route of elimination. A high margin of safety for prazosin has been established in safety evaluation studies in a variety of animal species.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMedDate not supplied

Synthesis and characterization of a radioiodinated photoaffinity probe for the alpha 1-adrenergic receptor.

A radioiodinated aryl azide analog, 2-[4-(4-azido-3- iodobenzoyl ) piperazin -1-yl]-4-amino-6, 7- dimethoxyquinazoline [(125I] CP65 ,526), of the highly selective alpha 1-adrenergic antagonist prazosin was synthesized and characterized using rat hepatic plasma membranes. Prior to photolysis, this ligand bound with high affinity (Kd 0.3 nM), stereoselectively and in a saturable manner to sites with an alpha 1-adrenergic specificity. When membranes pretreated with [125I] CP65 ,526 were irradiated with ultraviolet light, the ligand incorporated irreversibly into the receptor-binding sites, also with typical alpha 1-adrenergic specificity. Sodium dodecyl sulphate polyacrylamide gel electrophoresis of such labeled membranes followed by radioautography revealed major bands at Mr = 77,000, 68,000, and 59,000 daltons. Labeling of each of these bands was inhibitable by a variety of adrenergic ligands, stereoselectively and with a specificity typical of the alpha 1-adrenergic receptor. Smaller peptides with molecular weights of 42,000 and 31,000 daltons also displayed prazosin-inhibitable [125] CP65 ,526-binding. However, as the labeling of these protein species was not inhibitable by other adrenergic agonists or antagonists, they are unlikely to represent subunits of the receptor. Further evidence that [125I] CP65 ,526 incorporates covalently upon photolysis was the ability to specifically label immunoglobulin heavy and light chains of an antiserum that recognized both this ligand and the parent compound, prazosin. This new, radioiodinated, high-affinity probe should thus be uniquely valuable for the molecular characterization of the alpha 1-adrenergic receptor.

Affinity Labels↗
PubMedDate not supplied

Antibodies to the alpha 1- and alpha 2-selective antagonists prazosin and yohimbine as probes of the alpha-adrenergic binding sites.

Antibodies were raised against a newly synthesized analog (CP57,609) of the alpha 1-selective antagonist prazosin, and against the alpha 2-selective antagonist, yohimbine, by immunization of rabbits with antigens prepared by covalent linkage of these ligands to albumin. Competitive inhibition of [3H]prazosin binding to anti-CP57,609 antiserum by a variety of unlabeled ligands revealed a spectrum of antibody specificity, with alpha 1-selective agents competing more potently than alpha 2-selective ligands. In contrast, alpha 2-selective ligands competed more potently with the binding of [3H]yohimbine to the anti-yohimbine antiserum than alpha 1-selective agents. These respective antisera were subjected to affinity fractionation of a CP57,609- or yohimbine-Sepharose 4B resin. Fractions from the CP57,609 resin were eluted successively with phentolamine (10(-3)M), prazosin (10(-4)M), and guanidine (5M), and from the yohimbine resin with prazosin (10(-4)M), yohimbine (10(-4)M), and guanidine (5M). The binding profiles of these fractions differed, and in certain fractions the relative order of potency of adrenergic agents was almost identical to that observed with membrane alpha-adrenergic receptors. Moreover, using these eluted fractions as immunogens, antisera have been obtained which, in the initial bleeds, already possess antiidiotypic activity. These findings therefore suggest that affinity fractionation of antibodies raised against alpha 1- and alpha 2-selective antagonists may provide useful analogs for the further study of the ligand recognition properties of alpha-adrenergic receptors. Additionally, it is probable that antiidiotypic antisera will be developed which will recognize the alpha-adrenergic binding sites.

Animals↗