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Biomedical subjects

J J McNally

Publications and source records attributed to J J McNally.

15 recordsLinked to original sources
PubMed2001

Aminopyrazoles with high affinity for the human neuropeptide Y5 receptor.

1,3-Disubstituted-5-aminopyrazoles were prepared based on a lead compound found through high-throughput screening of our corporate compound library in an assay measuring affinity for the human neuropeptide Y5 receptor. The target compounds were prepared by cyclization of alpha-cyanoketones with appropriate hydrazines, followed by reduction and coupling to various sulfonamido-carboxylic acids. Several of these arylpyrazoles (e.g., 19 and 45) displayed high affinity for the human NPY Y5 receptor (<20nM IC(50)s).

Binding, Competitive↗
PubMed2000

N-acylated alpha-(3-pyridylmethyl)-beta-aminotetralin antagoinists of the human neuropeptide Y Y5 receptor.

Alpha-(3-Pyridylmethyl)-beta-aminotetralins were acylated with amino-piperidinyl and-pyrrolidinyl acetic acids, and with (aminomethyl)cyclohexanecarboxylic acid. Reaction with acyl chlorides, chloroformates, and isocyanates gave amides 8e, carbamates 9, and ureas 10, which bound to the Y5 receptor with nanomolar affinity. Congeners 11a and 11d containing a terminal benzimidazolone group were shown to be functional Y5 antagonists.

2-Naphthylamine↗
PubMed2000

N-(sulfonamido)alkyl[tetrahydro-1H-benzo[e]indol-2-yl]amines: potent antagonists of human neuropeptide Y Y5 receptor.

[3a,4,5,9b-Tetrahydro-1H-benzo[e]indol-2-yl]amines were prepared via reductive amination and concomitant cyclization of alpha-cyanomethyl-beta-aminotetralins. N-acylation with omega-sulfonamido-carboxylic acids and subsequent reduction afforded a series of N-(sulfonamido)alkyl[tetrahydro-1H-benzo[e]indol-2-yl]amines, which bound to the human neuropeptide Y Y5 receptor with nanomolar affinity.

Crystallography, X-Ray↗
PubMed1999

Potential anxiolytic agents. 3. Novel A-ring modified pyrido[1,2-a]benzimidazoles.

A variety of pyrido[1,2-a]benzimidazoles (PBIs) modified on the A-ring were prepared and evaluated for affinity to the benzodiazepine binding site on the GABA-A receptor and in animal models predictive of anxiolytic activity in humans. A-ring benzo-fused derivative 7 exhibited potent activity, as did the 6- and 7-pyrido compounds 3 and 4.

Animals↗
PubMed1999

Multi-component methodologies in solid-phase organic synthesis.

Solid-phase organic synthesis, particularly when used in conjunction with combinatorial techniques, is emerging as a revolutionary technology in chemistry. Multi-component reaction systems are particularly valued because several elements of diversity can be introduced in a single transformation thereby expanding the diversity of compound libraries. A variety of multi-component reactions have been successfully adapted for solid-phase technology as described in this review.

Chemistry, Organic↗
PubMed1993

Novel thieno[2,3-b]- and [3,4-b]pyrans as potassium channel openers. Thiophene systems--XVII.

The syntheses and antihypertensive activity of the thieno[3,4-b]pyran and thieno[2,3-b]pyran isosteres of the potassium channel opener (PCO) RWJ 26629 (+/- 2a) are reported. While the unsubstituted thiophene derivatives were active at 20 mg/kg, introduction of a strong electron withdrawing group in the 2-position of the thieno[3,2-b] series increased potency. Similar substitution on the thieno[3,4-b] series significantly lowered potency. Compounds 26 and 30 are approximately 5-fold more potent than the prototypic PCO cromakalim (+/- 1).

Animals↗
PubMed1992

Thiophene systems. 14. Synthesis and antihypertensive activity of novel 7-(cyclic amido)-6-hydroxythieno[3,2-b]pyrans and related compounds as new potassium channel activators.

The synthesis and antihypertensive activity of novel 7-(cyclic amido)-6-hydroxy-5,5-dimethylthieno[3,2-b]pyrans and related compounds are described. The compounds were tested for oral antihypertensive activity in spontaneously hypertensive rats (SHR) and selected compounds were evaluated in vitro for increases in 86Rb efflux in rabbit isolated mesenteric arteries. The effects on activity in SHR of lactam ring size, the presence of heteroatoms in the lactam ring, the relative stereochemistry at C-6 and C-7, and the substituents on the thiophene ring are examined. The best racemic compound in this series is 32, trans-5,6-dihydro-6-hydroxy-5,5-dimethyl-2-nitro-7-(2-oxopiperidin -1-yl)-5H- thieno[3,2-b]pyran, which is 10-fold more potent than cromakalim with an ED30 = 0.015 mg/kg in SHR. Compound 32 could be resolved and the antihypertensive activity determined to reside primarily in the (6S,7S)-(-)-enantiomer 41. Surprisingly, the elimination of water to give the enamides 50-52, thiophene isosteres of bimakalim, diminishes activity significantly.

Animals↗
PubMed1988

Thiophene systems. 9. Thienopyrimidinedione derivatives as potential antihypertensive agents.

A series of thieno[3,4-d]-, thieno[3,2-d]-, and thieno[2,3-d]pyrimidine-2,4-diones with (phenylpiperazinyl)alkyl substitution at N-3 have been synthesized and evaluated for antihypertensive effects in spontaneously hypertensive rats (SHR). These 49 compounds were compared to the vasodilator standards prazosin and the isosteric quinazoline-2,4-dione SGB 1534. Substitution at the 2-, 3-, or 4-position of the phenyl ring was examined, with that at the 2-position more potent than 4-substitution while the isomeric 3-substituted compounds were least potent. Neither alkylation nor acylation at the N-1 position improved the antihypertensive effects as compared to hydrogen. The three thienopyrimidine-2,4-diones (3-5) that contain a [(2-methoxyphenyl)piperazinyl]ethyl moiety at N-3 and hydrogen at N-1 were found to be potent oral antihypertensive agents in the SHR with doses (mg/kg, po) for reducing systolic blood pressure (SBP) by 50 mmHg (ED-50SBP) of 0.21, 0.19, and 1.0, respectively. The compounds 1-5 were further evaluated for alpha blocking potency by measuring the iv doses necessary to antagonize the phenylephrine pressor response by 50% (ED50) in the SHR. The ED50 values (micrograms/kg) are 10.4, 3.3, 1.7, 2.1, and 15.4, respectively. These results clearly show that all three thiophene systems have potent activity as antihypertensive agents and that 3 and 4 are more potent than 1 or 2 as alpha 1-antagonists in vivo.

Animals↗
PubMed1988

Cardiotonic agents. Synthesis and inotropic activity of a series of isoquinolin-3-ol derivatives.

A series of isoquinolin-3-ol derivatives (II) was prepared as analogues of the clinical cardiotonic agent bemarinone (ORF 16600, I). Although in many respects the structural requirements for the cardiotonic activity of II are similar to those of bemarinone, certain differences between the series were noted. Our structure-activity studies show that II is less sensitive to alkoxy-substitution effects than is I, and more significantly, 4-substitution of II by alkyl groups, halogen, or alkanecarboxylic acid derivatives enhances cardiotonic activity in II in contrast to I, wherein analogous substitution eliminated activity. A linear correlation between contractile force (CF) increase and cyclic nucleotide phosphodiesterase fraction III (PDE-III) inhibition by the title compounds was determined. The isoquinoline derivatives were characteristically short-acting cardiotonic agents with good potency and selectivity.

Animals↗
PubMed1988

Limited lateral spread of stromal edema in the human cornea fitted with a ('donut') contact lens with a large central aperture.

Topographical corneal thickness changes were monitored in 10 subjects who each wore a hydrogel contact lens with a large central aperture ("donut" lens) for 6 hours. Analysis of local corneal thickness changes indicates that no corneal swelling occurred in the central exposed area of the cornea, but significant swelling occurred in the area of the cornea covered by the lens. The lateral cut-off point of corneal swelling was well-defined, indicating that the contact lens-induced corneal edema did not spread laterally to the exposed area of the cornea over the six-hour wearing period. Swelling of the peripheral cornea covered by the lens was found to be significantly greater with a tightly-fitting, immobile donut lens than with a loosely-fitting lens, suggesting that tear mixing may explain in part the apparent averaging of edema during open-eye wear of hydrogel lenses of varying thickness profile. The possibility that lateral spread of lactate within the stroma may contribute to this apparent averaging of edema was not confirmed in this study. We suggest that rapid metabolism or elimination of lactate in the exposed region of the cornea, or evaporation through the central lens aperture, may have contributed to the maintenance of normal central corneal thickness during open-eye wear of the donut lens.

Adult↗
PubMed1985

Topographical corneal oedema.

Corneal thickness changes were monitored across the cornea in 10 subjects during 7 days continuous wear of 3 types of hydrogel contact lenses of different back vertex powers. Analysis of topographical corneal thickness changes indicates that the periphery of the cornea swells significantly less than the central cornea. The effect is more dramatic with higher levels of central corneal oedema, and with lenses of higher minus power, in spite of their thicker lens periphery. An anoxic stimulus was also found to produce greater central than peripheral corneal swelling, indicating that tear exchange under the periphery of the contact lens is not a significant factor in limiting peripheral corneal swelling. It was concluded that the topographical swelling profile is not contact lens-related, but reflects a reduced swelling capability of the peripheral cornea, due to physical restraint in the limbal region.

Adolescent↗
PubMedDate not supplied

Clinical aspects of topical application of dilute hydrogen peroxide solutions.

Because hydrogen peroxide (H2O2) is a widely used microbicidal agent for contact lens disinfection, it is important to assess its effect on ocular tissues at the levels that can be associated with the use of these systems. Three recently reported clinical studies provide new information on this subject: In the first study, the discomfort threshold for a range of H2O2 concentrations administered to the eye was explored. The mean thresholds for 10 subjects were 267 ppm H2O2 for 55% water content contact lenses soaked in the solution and 282 ppm for 38% water content contact lenses. Hydrogen peroxide disinfection systems are designed to have residual H2O2 concentrations in the eye of no more than 50-60 ppm, allowing for an adequate safety margin. The stinging occasionally reported after lens disinfection may be due to factors other than residual H2O2. In the second study, the rate of in vivo neutralization of H2O2 administered to the eye was studied. Removal of 50 ppm H2O2 from a hydrogel lens was completed within the first 30 seconds of human wear when the eyelids were held closed, and within 60 seconds during wideopen gaze, with blinking every 5 seconds. In the third study, the corneal permeability to fluorescein was determined in 10 subjects after dosing with 50 ppm H2O2, 500 ppm H2O2, as well as negative and positive controls. There was no significant difference between the negative control and the two H2O2 concentrations, whereas the positive control was different from all other treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗