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Biomedical subjects

S F Campbell

Publications and source records attributed to S F Campbell.

31 records · Page 2Linked to original sources
PubMed1988

2(1H)-quinolinones with cardiac stimulant activity. 1. Synthesis and biological activities of (six-membered heteroaryl)-substituted derivatives.

A series of (six-membered heteroaryl)-substituted 2(1H)-quinolinones (1) was synthesized, and structure-activity relationships for cardiac stimulant activity were determined. Most compounds were prepared by acidic hydrolysis of a heteroaryl-2-methoxyquinoline obtained by palladium-catalyzed cross-coupling methodology. Direct reaction of a pyridinylzinc reagent with a 6-haloquinolinone also proved successful. In anesthetized dogs, 6-pyridin-3-yl-2(1H)-quinolinone (3; 50 micrograms/kg) displayed greater inotropic activity (percentage increase in dP/dt max) than positional isomers (2, 4-6), and potency was maintained with either mono- (13, 15) or di- (16) alkylpyridinyl substituents. Introduction of a 4- (24) or 7- (25) methyl group into 3 reduced inotropic activity, whereas the 8-isomer (26) proved to be the most potent member of the series. Compound 26 and the 2,6-dimethylpyridinyl analogue (27) were approximately 6 and 3 times more potent than milrinone. Several quinolinones displayed positive inotropic activity (decrease in QA interval) in conscious dogs after oral administration (1 mg/kg), and 26, 27 were again the most potent members of the series. Compound 27 (0.25, 0.5, 1.0 mg/kg po) demonstrated dose-related cardiac stimulant activity, which was maintained for at least 4 h. No changes in heart rate were observed. Compounds 3, 4, 26, and 27 also selectively stimulated the force of contraction, rather than heart rate, in the dog heart-lung preparation. For a 50% increase in dP/dt max with 27, heart rate changed by less than 10 beats/min. In norepinephrine contracted rabbit femoral artery and saphenous vein, 27 produced dose related (5 X 10(-7) to 5 X 10(-4) M) vasorelaxant activity. The combined cardiac stimulant and vasodilator properties displayed by 27, coupled with a lack of effect on heart rate, should be beneficial for the treatment of congestive heart failure.

Animals↗
PubMed1988

2,4-Diamino-6,7-dimethoxyquinazolines. 4. 2-[4-(substituted oxyethoxy) piperidino] derivatives as alpha 1-adrenoceptor antagonists and antihypertensive agents.

A series of 4-amino-6,7-dimethoxy-2-[4-(substituted oxyethoxy)piperidino] quinazoline derivatives (2) was synthesized and evaluated for alpha-adrenoceptor affinity and antihypertensive activity. Most compounds showed binding affinities within the nanomolar range for alpha 1-receptors, although 25 and 26 showed enhanced potency (Ki, ca. 1.5 X 10(-10) M), equivalent to that of prazosin. Series 2 also displaced [3H]clonidine from alpha 2-adrenoceptors, but at relatively high doses of 10(-6) M, and selectivity for alpha 1 sites still predominated. In a rabbit pulmonary artery preparation, 12, 16, and 25 were potent antagonists of the alpha 1-mediated, postjunctional vasoconstrictor activity of norepinephrine with no effect at the prejunctional alpha 2 sites which modulate transmitter release. Physicochemical measurements gave a pKa of 7.63 +/- 0.10 for 12, and N-1 protonation will be favored (60%) at physiological pH to provide the alpha 1-adrenoceptor pharmacophore, 28. Antihypertensive activity of series 2 was evaluated following oral administration to spontaneously hypertensive rats, and blood pressure was measured after 1 and 6 h. Compounds 12, 13, 16, 23, and 37 displayed moderate efficacy and duration of action in lowering blood pressure, but the plasma half-life (ca. 2 h) of 16 in dogs was not compatible with potential once-daily administration in humans.

Adrenergic alpha-Antagonists↗
PubMed1988

2,4-Diamino-6,7-dimethoxyquinoline derivatives as alpha 1-adrenoceptor antagonists and antihypertensive agents.

A series of 2,4-diamino-6,7-dimethoxyquinoline derivatives (2), prepared by LDA- or ZnCl2-mediated intramolecular cyclization of an N-[1-(dialkylamino)ethylidene]-2-cyano-4,5-dimethoxyaniline (3), was evaluated for alpha-adrenoceptor affinity and antihypertensive activity. Most compounds displayed high in vitro binding affinities (Ki's, 10(-10) M) for alpha 1-adrenoceptors with alpha 1-/alpha 2-selectivity ratios of at least 10,000. 4-Amino-2-[4-(2-furoyl)piperazin-1-yl]-6,7-dimethoxyquinoline++ + (14) proved to be the most potent member (Ki = 1.4 X 10(-10) M) of series 2, and displayed no activity at alpha 2-adrenoceptor binding sites at concentrations up to 10(-6) M. In the rabbit pulmonary artery, 14 was a highly potent (pA2 = 9.76 +/- 0.26) competitive antagonist of the alpha 1-mediated vasoconstrictor action of noradrenaline and was some 20 times more active than prazosin. pKa measurements confirmed that, at physiological pH, N-1 protonation of series 2 would efficiently provide 1b, a key pharmacophore for alpha 1-adrenoceptor recognition. Antihypertensive activity for series 2 was evaluated after oral administration (3 mg/kg) to spontaneously hypertensive rats (SHR) and falls in blood pressure were determined at 1 and 4.5 h. Various quinoline derivatives (2) proved to be effective antihypertensive agents in SHR, with both efficacy and duration of action at least equivalent to prazosin, and 14 displayed the most favorable overall profile. These observations are consistent with the high affinity and selectivity displayed by series 2 for postjunctional alpha 1-adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMed1988

1,3-Diamino-6,7-dimethoxyisoquinoline derivatives as potential alpha 1-adrenoceptor antagonists.

Treatment of 2-methyl-4,5-dimethoxybenzonitrile (3) with LDA followed by reaction with an N,N-disubstituted cyanamide provided a series of 1,3-diamino-6,7-dimethoxyisoquinolines (2), which were evaluated for alpha-adrenoceptor binding affinity and antihypertensive activity. 1-Amino-3-(dimethylamino)-6,7-dimethoxyisoquinoline (4) showed no significant affinity (Ki much greater than 10(-6) M) for alpha 1-adrenoceptors, while the corresponding 3-(2-furoylpiperazin-1-yl) analogue (8; Ki = 1.6 X 10(-7) M) was some 1000-fold less potent than prazosin. pKa data showed that N-2 protonation (34%) of 4 (pKa = 7.1) would occur at physiological pH, in agreement with X-ray crystallographic analysis of 8.HCl. Comparison of positive charge distribution following protonation of 4 with the corresponding quinoline and quinazoline cations confirmed N-1 protonation is required for these heterocyclic nuclei to bind efficiently to the alpha 1-adrenoceptor. Computer-assisted comparison of the X-ray structures of 8 and prazosin suggested that the 4.0 kcal/mol difference in alpha 1-adrenoceptor binding energies was largely due to salt-bridge formation (ca. 3.0 kcal/mol) between the protonated quinazoline and the receptor protein. None of the isoquinolines (2) proved to be effective antihypertensive agents in rats even when administered at relatively high doses (10 mg/kg). These results support the hypothesis that the antihypertensive activity of prazosin, doxazosin, and related derivatives derives solely from alpha 1-adrenoceptor blockade.

Adrenergic alpha-Antagonists↗
PubMed1987

The geometries of interacting arginine-carboxyls in proteins.

The geometries are reported for interacting arginine-carboxyl pairs obtained from 37 high resolution protein structures solved to a resolution of 2.0 A or better. The closest interatomic distance between the guanidinium and carboxyl is less than 4.2 A for 74 arginine and carboxyl groups, with the majority of these lying within hydrogen-bonding distance (2.6-3.0 A). Interacting pairs have been transformed into a common orientation, and arginine-carboxyl, and carboxyl-arginine geometries have been calculated. This has been defined in terms of the spherical polar angles T theta, T phi, and the angle P, between the guanidinium and carboxyl planes. Results show a clear preference for the guanidinium and carboxyl groups to be approximately coplanar, and for the carboxyl oxygens to hydrogen bond with the guanidinium nitrogens. Single nitrogen-single oxygen is the most common type of interaction, however twin nitrogen-twin oxygen interactions also occur frequently. The majority of these occur between the carboxyl oxygens and the NH1 and NE atoms of the arginine, and are only rarely observed for NH1 and NH2. The information presented may be of use in the modelling of arginine-carboxyl interactions within proteins.

Arginine↗
PubMed1987

2,4-diamino-6,7-dimethoxyquinazolines. 1. 2-[4-(1,4-benzodioxan-2-ylcarbonyl)piperazin-1-yl] derivatives as alpha 1-adrenoceptor antagonists and antihypertensive agents.

A series of 4-amino-2-[4-(1,4-benzodioxan-2-ylcarbonyl)piperazin-1 -yl]-6, 7-dimethoxyquinazoline derivatives was synthesized for evaluation as alpha-antagonists and antihypertensive agents. Most compounds displayed high (nM) binding affinity for alpha 1-adrenoceptors with no significant activity at alpha 2-sites. Selective antagonism of the alpha 1-mediated vasoconstrictor effects of norepinephrine is also characteristic of the series. Structure-activity relationships for alpha 1-adrenoceptor affinity are presented, and structural similarity between the 2,4-diamino-6,7-dimethoxyquinazoline nucleus and norepinephrine is established. An alpha 1-receptor model is presented in which charge-reinforced hydrogen bonding is important for binding of both antagonist and agonist molecules. Antihypertensive activity was evaluated after oral administration (5 mg/kg) to spontaneously hypertensive rats, and several compounds displayed similar efficacy to prazosin when assessed after 6 h. On the basis of alpha 1-adrenoceptor affinity/selectivity in vitro and duration of antihypertensive action in vivo, compound 1 (doxazosin) was selected for further evaluation and is currently progressing through phase III clinical trials.

Adrenergic alpha-Antagonists↗
PubMed1987

2,4-Diamino-6,7-dimethoxyquinazolines. 2. 2-(4-Carbamoylpiperidino) derivatives as alpha 1-adrenoceptor antagonists and antihypertensive agents.

A series of 4-amino-2-(4-carbamoylpiperidino)-6,7-dimethoxyquinazolines (2) were synthesized and evaluated for alpha-adrenoceptor affinity and antihypertensive activity. These compounds displayed high binding affinity (Ki, 10(-9)-10(-10) M) and selectivity for alpha 1-adrenoceptors in vitro, and 12, 14, 21-26, and 29 showed similar potency to prazosin. Compounds 26 and 28 were also shown to be competitive antagonists of the postjunctional, vasoconstrictor action of norepinephrine with no significant activity at prejunctional alpha 2-sites. The high binding affinity for series 2 is rationalized in terms of enhanced basicity of the quinazoline nucleus (pKa's: 12, 7.38; 26, 7.53; prazosin, 6.8) and hydrophobic interactions of the carbamoyl substituents. Molecular mechanics calculations and computer-assisted superimposition suggest that the quinazoline 2-substituents in prazosin and 2 occupy the alpha 1-adrenoceptor site in different manners. Antihypertensive activity was evaluated after oral administration (5 mg/kg) to spontaneously hypertensive rats, and 11, 15, 21, 22, and 26 displayed sustained prazosin-like efficacy at the 6-h time point. The high alpha 1-adrenoceptor affinity demonstrated by series 2 in vitro suggests that these marked, and prolonged, falls in blood pressure result from selective blockade of the alpha 1-mediated vasoconstrictor effects of norepinephrine.

Adrenergic alpha-Antagonists↗
PubMed1987

2,4-Diamino-6,7-dimethoxyquinazolines. 3. 2-(4-Heterocyclylpiperazin-1-yl) derivatives as alpha 1-adrenoceptor antagonists and antihypertensive agents.

A series of 4-amino-6,7-dimethoxy-2(4-heterocyclylpiperazin-1-yl)quinazolines (3) was prepared and screened for alpha-adrenoceptor affinity and antihypertensive activity. These quinazoline derivatives showed high binding affinity (ca. 10(-10) M) and selectivity (greater than 10,000) for alpha 1-adrenoceptors in vitro, with no relevant activity at alpha 2 sites. Several compounds displayed similar activity to prazosin (Ki = 1.9 X 10(-10) M) while the dimethoxytriazine derivative 30 (Ki = 8 X 10(-11) M) was more potent. Like prazosin (pA2 = 8.37 +/- 0.24), 30 proved to be a potent (pA2 = 8.63 +/- 0.15), competitive antagonist of the alpha 1-mediated vasoconstrictor action of norepinephrine. The high binding affinity of series 3 is most likely due to formation, at physiological pH, of the protonated, alpha 1-adrenoceptor pharmacophore 33, coupled with efficient hydrophobic interactions of the quinazoline 2-substituents. Computer-assisted super-imposition of prazosin and 30 showed little structural correspondence between the furoyl and dimethoxytriazine moieties, and specific interactions of these molecular fragments with the receptor protein appear unlikely. Series 3 was evaluated for antihypertensive activity after oral administration (5 mg/kg) to spontaneously hypertensive rats, and blood pressure was recorded after 1 and 6 h. In vivo performance was markedly dependent on the nature of the distal heterocyclic system and various derivatives demonstrated superior or equivalent profiles to prazosin, with respect to both antihypertensive efficacy and duration of action.

Adrenergic alpha-Antagonists↗
PubMed1987

Calcium channel blocking properties of amlodipine in vascular smooth muscle and cardiac muscle in vitro: evidence for voltage modulation of vascular dihydropyridine receptors.

Amlodipine was twice as potent as nifedipine at inhibiting Ca2+-induced contractions in depolarised rat aorta (IC50 1.9 nM vs. 4.1 nM) but, unlike nifedipine, displayed a very slow onset of action. Contractions induced by depolarising steps with 45 mM K+ were much less potently blocked by amlodipine (IC50 19.4 nM), whereas the potency of nifedipine was little changed (IC50 7.1 nM). This difference may be explained by a modulated receptor hypothesis, similar to that described for cardiac muscle, in which block of vascular calcium channels by dihydropyridines is enhanced at depolarized membrane potentials, such voltage-dependence only being apparent with a slow-acting drug such as amlodipine. Recovery from amlodipine block of K+-responses in rat portal vein after drug washout was also very slow. Amlodipine and nifedipine blocked phenylephrine-induced contractions of the rat aorta with potencies similar to those against depolarisation-induced responses. Negative inotropic potencies of amlodipine and nifedipine in perfused guinea pig hearts were approximately one-tenth those against Ca2+-induced contractions in rat aorta. Amlodipine caused complete block of guinea pig papillary muscle single-cell slow action potentials at a concentration (5 microM) that had no effect on upstroke velocity of normal, fast potentials but reduced the duration of the plateau phase.

Action Potentials↗
PubMed1986

Long-acting dihydropyridine calcium antagonists. 1. 2-Alkoxymethyl derivatives incorporating basic substituents.

A series of dihydropyridines substituted at the 2-position by basic side chains are described and their potencies as calcium antagonists listed. One compound, 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5- methoxycarbonyl-6-methyl-1,4-dihydropyridine (17, amlodipine) was found to be comparable in potency to nifedipine and to have an elimination half-life of 30 h in dogs. Oral bioavailability approached 100%, and hemodynamic responses were gradual in onset and long-lasting in effect. The two enantiomers have been prepared, and the bulk of the activity was found to reside with the (-) isomer, 18. X-ray crystallographic studies, carried out on a close analogue of 17, suggest the existence of a weak hydrogen bond between the side-chain oxygen and the proton on the ring nitrogen.

Amlodipine↗
PubMed1986

Doxazosin, a case history.

Demonstration that the antihypertensive activity of prazosin resulted from blockade of postjunctional alpha 1-adrenoceptors stimulated interest in identifying the structural basis for this novel pharmacological profile. SARs suggested that 2,4-diamino-6,7-dimethoxyquinazoline was the pharmacophore for alpha 1-adrenoceptor recognition and that receptor occupancy was similar to noradrenaline. This model stressed the importance of charge-reinforced hydrogen bonding rather than particular roles played by individual nitrogen atoms. Modification of the quinazoline 2-substituent influenced alpha 1-adrenoceptor affinity and antihypertensive activity, particularly duration of action. These studies led to a novel series of quinazoline-benzodioxanoyl derivatives from which doxazosin was selected for detailed evaluation. Doxazosin is a potent, selective alpha 1-adrenoceptor antagonist which produces long-lasting antihypertensive effects in laboratory animals, with little effect on heart rate. In man, the plasma half-life of doxazosin is approximately 10 hr., consistent with clinical evidence that once-daily administration provides 24 hr. blood pressure control.

Animals↗
PubMed1969

Total synthesis of the racemic form of the second juvenile hormone (methyl 12-homojuvenate) from the cecropia silk moth.

Methyl cis-10-epoxy-3,7,11-trimethyl-trans,trans-2,6-tridecadienoate has been stereoselectively synthesized in 12 steps starting from methyl trans-gamma-bromo-beta,beta-dimethylacrylate and 1-acetyl-1-methylcyclopropane. The final product proved to be identical with the second, less abundant juvenile hormone (methyl 12-homojuvenate) isolated from the Cecropia silk moth. The biological activities of the compound were evaluated in various insects.

Journal Article↗