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The authors explored the role of Cyclo [His-Pro] (CHP) in 50 adolescents who fulfilled DSM III diagnostic criteria for anorexia nervosa and bulimia. CHP, a relatively new neuro modulator which has a role in inducing satiety, was assayed in serum during routine blood work. CHP levels correlated significantly with weight in restrictor (AN-R) (R = -0.449, P less than 0.05) and bulimic anorexics (AN-B) (R = +0.489, P less than 0.01). There was no significant correlation in normal-weight bulimics (NWB) (R = +0.556, P less than 0.01). It did not correlate with weight in a depressed control group. Longitudinal data on six patients showed a similar relationship between weight, purging and CHP binge/purge activity and/or weight changes of around 2 kilograms correlated with average CHP changes of 42%. Clinical material suggests changes in satiety during CHP changes consistent with a satiety disturbance model of these disorders.

Once considered only mediators of inflammation, autacoids, (histamine, prostaglandins and beta-mimetic catecholamines) have been found to be generated during specific early and late phases of immunity. They need sufficient concentrations to affect immunocytes and can modulate immunity usually by inhibiting it. Receptors for the autacoids on the immunocytes are nonrandomly distributed. A small portion of T suppressor cells always appear to have receptors on them, but precursor B cells and precursors of T cells that produce lymphokines or are responsible for cytolysis do not. Instead, as these cells mature they develop their autacoid receptors. With one exception, the function of the immunocytes is inhibited by the effects of autacoids. Again, in all but one instance, that inhibitory modulating effect is mediated by and directly proportional to the intracellular concentrations of cyclic adenosine monophosphate (AMP) generated by the autacoid. The clinical implications of these observations are beginning to be appreciated. One of them is that pharmacologic antagonists of the autacoids can have predictable but hitherto unanticipated effects on immune functions. It is inconceivable that these effects will not have clinical value.

A novel series of N-aminoalkyl congeners and model derivatives of norepinephrine has been synthesized. Compounds that were structurally related to epinephrine were prepared from fully protected intermediates. Alternatively, isoproterenol-related compounds were synthesized via reductive amination of preformed methyl ketone derivatives with norepinephrine. The beta-adrenergic activities of these new compounds were assessed through measurement of intracellular cyclic AMP accumulation in S49 mouse lymphoma cells and displacement of iodocyanopindolol (ICYP) from membrane preparations. Congeners that contained an underivatized primary amine function exhibited virtually no activity in these assays. However, when this amine function was acylated (e.g., to an amide, carbamate, urea, sulfonamide, etc.), the products exhibited generally increased beta-adrenergic activity, which was, however, strongly dependent on the nature of the acylating group and also the length of the spacer. In particular, a benzyl carbamate derivative containing a branched, seven-carbon spacer group was 40 times more potent than isoproterenol in the in vitro S49 assay.

A new series of catecholamines has been prepared in which the N-alkyl substituent of dl-epinephrine or dl-isoproterenol has been extended by a methylene chain terminated by a hydroxyl group or derived functionality (e.g., carbamate or ester). These functionalized catecholamines (congeners) and model compounds were prepared with the goal of eventual attachment to polymeric carrier molecules. The beta-adrenergic agonist activity of the derivatives was evaluated in vitro by measuring the intracellular accumulation of cyclic AMP in S49 mouse lymphoma cells and by the displacement of iodocyanopindolol (ICYP). A n-butylcarbamate derivative (compound 15) was the most active compound in this series with a potency 190 times greater than dl-isoproterenol in the S49 assay. The biological results indicate that minor modifications in structure in the N-alkyl substituent of the catecholamine can influence the pharmacologic activity.

A series of analogues of N,N-di-n-propyldopamine (DPDA) in which the 3-hydroxyl group was replaced by bioisosteric groups was prepared and evaluated for D1- and D2-receptor affinity. The 3-methane-sulfonamide analogue (18) had a higher affinity for the D2 receptor than DPDA and was more selective for the D2 receptor. The 3-formamide derivative (15) also retained significant D2 affinity. Both of these compounds demonstrated in vivo cardiovascular and renal profiles in an anesthetized rat model that were consistent with selective D2-receptor agonism.

A series of functionalized catecholamines (congeners) has been synthesized in which, formalistically, the N-isopropyl group of isoproterenol has been extended by a linear alkyl chain of varying length, terminated by a carboxy group or a substituted amide. The compounds were prepared generally via the reductive amination of norepinephrine with a keto acid or a preformed keto amide. An alternate synthesis of the model amide derivatives, involving activation of the carboxylic acid congeners and coupling with amines, was complicated in the case of short-chain derivatives by facile cyclization to lactams. In vitro evaluation of these compounds as potential beta-adrenergic agonists has shown that, while the carboxylic acid congeners have relatively low potencies, the model amide derivatives have potencies that are highly dependent on both the length of the alkyl chain and also the nature of the substituent on the amide. In general, aromatic amides are the most potent, although the nature and position of substituents on the aromatic group dramatically influences their potency. The implications of these studies, in terms of general beta-adrenergic drug design and also the attachment of the carboxylic acid congeners to carriers, are discussed.

Intracerebroventricular administration of prostaglandins E1 or E2 was shown to block, while PGF2alpha increased the incidence of tonic convulsion due to electroshock in mice. The Prostaglandins were administered intracerebroventicularly (i.c.v.) to conscious mice by a modification of Haley and McCormick's method (1) prior to a transcorneal maximal electroshock (MES) or a transcorneal supra-maximal electroshock (SMES). PGE1 and PGE2 i.c.v. blocked the tonic hindlimb extension (THE) and protected the animals from death induced by MES with ED50's for PGE1 and PGE2 for inhibition of the THE of 6.6 (4.3--12.0) microgram/mouse i.c.v. and 13.3 (8.9--22.4) microgram/mouse i.c.v. respectively. When PGE2 was administered intraperitoneally (i.p.) in doses as high as 4.0 mg/kg it did not block the THE. However, the duration of the THE as well as the mortality were reduced by doses of 0.5--4.0 mg/kg PGE2 i.p.. Both PGE1 and PGE2 were shown to cause a dose related significant (p less than .001) decrease in the duration of the THE with SMES in doses of 1--10 microgram/mouse i.c.v. for PGE1 and 2--40 microgram/mouse i.c.v. for PGE2. PGF2alpha, administered i.c.v. prior to a transcorneal electroshock equivalent to a current at the ED1 level, increased the incidence of the THE as well as the mortality in doses of 20--50 microgram/mouse.

The gastric antisecretory and gastrointestinal (GI) motility activity of the natural and unnatural allenic isomers and degradation products of enprostil (methyl(+/-)-7-[(1R*,2R*,3R*)-3-hydroxy-2-[(E)-(3R*)-3-hydroxy-4-phenoxy - 1-butenyl]-5-oxocyclopentyl]-4,5-heptadienoate, RS-84135-004) were studied in the rat. The natural R-allenic isomer of enprostil was the most potent antisecretory compound. The 8-iso-enprostil, enprostil free acid, and the 5-acetylene isomer had somewhat less activity while the other compounds were relatively inactive. The natural and unnatural allenic isomers increased intestinal dye transit with the same rank potency as the gastric antisecretory activity. Enprostil, 8-iso-enprostil, prostaglandin A-enprostil and enprostil free acid, all increased intestinal dye transit.

A series of monodisperse oligopeptide conjugates related to the catecholamine, isoproterenol, has been synthesized. The peptide carrier molecules used were synthesized by stepwise and fragment condensation techniques and ranged in size from a single, blocked amino acid derivative to isomeric pentapeptides. The amino acid compositions and sequences of the carriers were chosen so as to provide specific information concerning the effects of molecular weight, hydrophilic/hydrophobic balance, charge, etc., on the biological activity of the final conjugates. The common point of attachment for the drug in all carriers was a p-aminophenylalanine residue. The peptide-catecholamine conjugates were prepared via the attachment of carboxyl-containing catecholamine congeners, to the peptide carriers by techniques described previously. The conjugates were purified rigorously by chromatographic techniques and characterized by high-field n.m.r. spectroscopy.

Previous studies in our laboratory suggested that synthetized derivatives of isoproterenol and histamine could create agonists more potent and receptor and/or tissue selective than the parent compound. In the present study we have evaluated the hypothesis that our results with isoproterenol and histamine derivatives could be extended to include beta-adrenergic antagonists. With this purpose in mind, fourteen derivatives of propranolol and practolol were synthesized and tested in four in vitro systems. The congeners and conjugates were tested using biologic assays (blocking of cAMP accumulation) and/or radioligand binding assays in S-49 lymphoma cells and in rat adipocytes, heart and lung which contain beta 1 and/or beta 2 receptors. Our results indicate that structural modifications distant from the pharmacophore alter the pharmacologic profile of the parent compound. The relative potencies of the derivatives were dependent upon several key factors including the length of the methylene spacer chain and the nature of the substituents on the aromatic ring. The presence of a spacer group with four methylenes resulted in the most active compound in each series when tested on S-49 cells. The derivatives with a paramethyl toluidide group were more potent than the derivatives with a trifluoromethyl toluidide group. The dipeptide derivatives were more potent on adipocyte than S-49 cells, suggesting a preference for beta 1 receptors. Some of the same modifications that led to altered potency and which resulted in an increased receptor and/or tissue selectivity using the progenitors isoproterenol or histamine did extrapolate to the beta blockers. Our data suggest that alterations in receptor and/or tissue selectivity must be imparted by the carrier moiety of the drug and may be related to the biochemical microenvironment of the receptors.

The effects of enprostil (+/-)-7-[(1R*,2R*,3R*)-3-hydroxy-2-[(E)-(3R*)-3-hydroxy-4-phenoxy-1- butenyl]-5-oxocyclopentyl]-4,5-heptadienoate) were studied on cardiovascular and respiratory parameters in the dog and on hematologic parameters in the rat, monkey, and human. Anesthetized dogs were instrumented to allow measurement of heart rate, systemic blood pressure, respiratory rate or tracheal pressure, and ventricular contractile force after intragastric (i.g.) or intravenous (i.v.) administration of enprostil in the presence or absence of autonomic challenges. The effects of intraduodenal (i.d.) enprostil on arterial and venous PO2, PCO2, and pH; respiratory rate, flow rate, and volume; blood pressure (b.p.); and heart rate were also examined. Enprostil i.v. (0.3-10 micrograms/kg) significantly increased tracheal pressure in a dose-dependent manner, but minimally altered b.p., heart rate, and ventricular contractile force. Enprostil i.v. (1-10 micrograms/kg) significantly inhibited pressor and depressor responses to several autonomic challenge agents at the highest dose level, indicative of a nonspecific inhibitory effect on b.p. responses. Cardiovascular effects of enprostil (1-100 micrograms/kg i.g.) were absent. Enprostil (10-3,000 micrograms/kg i.d.) had no noteworthy effects on respiratory parameters in the dog. Platelet aggregation effects of enprostil were studied in vitro using platelet rich plasma (PRP) from the rat, monkey, and human; whole blood clotting time and prothrombin time after oral enprostil were studied in the rat; and ex vivo effects on platelet activation were studied in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Several [(1H-imidazol-1-yl)methyl]- and [(3-pyridinyl)methyl] pyrroles were prepared and evaluated in vitro as thromboxane synthetase inhibitors in human platelet aggregation studies. A number of structures, e.g. 10b,f,g,i (respective IC50 values: 1 microM, 50 nM, 42 nM, 44 nM) showed superior in vitro inhibition of TXA2 synthetase when compared to the standard dazoxiben (1). However, it was found that in vitro potency did not translate into nor correlate with in vivo activity when these compounds were evaluated in mice in a collagen-epinephrine-induced pulmonary thromboembolism model. (E)-1-Methyl-2-[(1H-imidazol-1-yl)methyl]-5-(2-carboxyprop-1-enyl) pyrrole (10b) was found to offer protection against collagen-epinephrine-induced mortality in mice, thereby demonstrating that oral administration is an effective route for absorption of this drug. Additional evidence for the oral effectiveness of 10b in lowering serum TXB2 levels was obtained by performing ex vivo radioimmunoassay experiments with rats. A 13-week study of 10b in rats with reduced renal mass was conducted in order to evaluate the role of TXA2 production in hypertension and renal dysfunction. Although serum and urinary TXB2 levels in rats were found to be lowered during this study by 10b, the levels of urinary protein excretion remained comparable to that of the control group.