Biomedical subjects

M Urbanski

Publications and source records attributed to M Urbanski.

7 recordsLinked to original sources

PubMed2001

Discovery of the first non-peptide antagonist of the motilin receptor.

A first-in-class non-peptide antagonist of the motilin receptor was identified through electronic screening of our corporate database against a 3D pharmacophore. The pharmacophore was developed from the motilin 22 residue endogenous peptide using NMR structural data, principles of peptide folding, and peptide structure activity relationships. The NMR data supported helical content within the peptide, and both the hydrophobic staple and N-capping box motifs were identified in the motilin sequence. The conformational features of these motifs were imposed on the peptide structure, providing a constrained conformer as a starting point for database searching. A trisubstituted cyclopentene lead was identified directly from the electronic search. Compounds in this series inhibit the binding of 125I-motilin to human antral smooth muscle membrane and antagonize motilin-induced intracellular calcium mobilization in cells expressing the human motilin receptor. A potent compound developed through optimization, RWJ 68023, is active in binding and cell-based functional assays and is also effective in inhibiting motilin-induced contractility in segments of rabbit duodenum. This orally active compound is currently undergoing clinical evaluation for the treatment of gastrointestinal disorders associated with altered motility.

Amino Acid Sequence↗

PubMed1994

T cell-derived antigen-specific humoral immune response. II. Further characterization of the response and the antigen binding T cell immunoproteins.

Murine T lymphocyte-derived proteins which bind nominal antigen specifically (TABM) were detected in serum during a humoral immune response to bovine serum albumin. The TABM response was observed only when the adjuvants polyadenylic:polyuridylic acid complex (poly(A: U)), Freund's complete adjuvant or Titermax were used concurrently with antigen to immunize. When poly(A:U) was used, higher doses of antigen were optimal to stimulate TABM production than those required to stimulate immunoglobulin production. The binding of TABM in the serum of BSA-immunized mice to BSA in solid phase was inhibited specifically by 10-fold more BSA than that required to inhibit BSA-specific immunoglobulins suggesting that TABM have much less affinity for antigen than immunoglobulins. Immunoblotting of TABM in serum from BSA-immune mice, which bind BSA, demonstrated that these serum TABM are comprised of M(r) 110,000 polypeptides linked by disulfide bonds. Antigen-specific proteins in a lysate of an NP-specific T cell hybrid inhibited the recognition of serum TABM by anti-TABM antiserum while a lysate of a B cell hybridoma was not inhibitory, and serum TABM were adsorbed by monoclonal antibodies to TCR-C beta. These results provide more evidence that serum TABM may be a soluble analogue of the T cell receptor for antigen.

Adjuvants, Immunologic↗

PubMed1992

Appearance of T lymphocyte-derived proteins specific for the immunizing antigen in serum during a humoral immune response.

Some T lymphocytes produce extracellular proteins that bind nominal antigen specifically (TABM), and these proteins exhibit potent immunoregulatory activity. We have utilized an ELISA for Ag binding by Ag-specific TABM to detect and quantitate the appearance of Ag-specific TABM in murine serum during a humoral Ir to protein Ag. The TABM response was specific for the inducing Ag, stronger and more rapid during a secondary response, and temporally distinct from the appearance of Ig. The non-Ig serum TABM were bound by mAb specific for TCR-alpha chains and isolated by affinity for Ag were Mr 110,000 polypeptides. The TABM response did not occur in scid/scid mice unless the mice were reconstituted with thymocytes and thymocyte-reconstituted scid/scid mice produced TABM, but did not produce Ig. The results suggest that soluble TABM are an Ag-specific humoral manifestation of the Ir of some T lymphocytes.

Animals↗

PubMed1992

Specific antigen binding by proteins secreted by an antigen-specific T cell hybrid.

Antigen-specific molecules secreted by a murine T cell hybrid specific for azobenzene arsonate (ABA) were purified from ascites fluid by ion exchange chromatography and affinity for antigen. The antigen-specific proteins were purified 250 fold and were resolved predominantly as Mr 110,000 polypeptides by reduction and SDS-polyacrylamide gel electrophoresis. The ability of these molecules to bind antigen was analyzed by an ELISA using antigen-coated microtiter trays. Binding of the T cell proteins to antigen was detected with antisera specific for the proteins. Antigen binding to ABA-ovalbumin but not ovalbumin was optimal at 37 degrees C and protein derived from another T cell hybrid did not bind ABA-ovalbumin. Solid phase antigen binding was inhibited specifically by soluble ABA-ovalbumin, indicating that these T cell-derived proteins bind nominal antigen in the solid or liquid phase. It is suggested that these proteins represent a soluble, antigen specific manifestation of some T cell function.

Animals↗

PubMed1988

Synthesis of (aryloxy)alkylamines. 1. Novel antisecretory agents with H+K+-ATPase inhibitory activity.

A series of heterocyclic (aryloxy)alkylamines of structures II and III were prepared and found to possess gastric antisecretory activity. Of the variety of substituted thiazoles, benzoxazoles, and benzothiazoles prepared, thiazole 18, benzoxazole 32, and benzothiazole 47 exhibited gastric antisecretory potency comparable to that of ranitidine in vivo in the pylorous ligated rat model. In an isolated rabbit parietal system, the series of thiazoles, benzoxazoles, and benzothiazoles also demonstrated similar potency to that of ranitidine toward the inhibition of both histamine-stimulated and dcAMP-stimulated uptake of amino[14C]pyrine. These compounds inhibited the H+K+-sensitive ATPase enzyme in isolated gastric microsomes. A direct correlation existed between inhibition of 14C uptake, in vivo antisecretory activity, and inhibition of the H+K+-ATPase enzyme. The more potent antisecretory compounds 18, 32, and 47 were also the more potent enzyme inhibitors. These data suggest that the mechanism responsible for the observed in vitro and in vivo gastric antisecretory activity, in these series of compounds, is a consequence of the inhibition of the H+K+-sensitive ATPase enzyme.

Adenosine Triphosphatases↗

PubMed1988

Synthesis of (aryloxy)alkylamines. 2. Novel imidazo-fused heterocycles with calcium channel blocking and local anesthetic activity.

A series of imidazo-fused heterocycles substituted with an aryloxy)alkylamine side chain were prepared as modifications to butoprozine (I) and found to possess calcium channel blocking activity similar in potency to that of bepridil in trachea smooth muscle and similar to that of verapamil in nitrendipine binding affinity in rabbit cardiac muscle. Of the various imidazo-fused heterocycles prepared, the imidazo[1,2-a]pyridines were also found to be potent local anesthetic agents. While most compounds in this series were equipotent to lidocaine in our initial screen, compounds 2 and 35 showed local anesthetic activity approximately 100 times more potent than lidocaine in our preliminary assays. These compounds represent a novel structural class of local anesthetic agents, and compound 2 is under further investigation.

Amines↗

PubMedDate not supplied

Microgenia as a factor making endotracheal intubation impossible.

The authors report a case of microgenia which made endotracheal intubation impossible in a patient with pharyngeal stenosis. It is suggested that laryngological examination should precede the operation and when endotracheal intubation is impossible tracheostomy should be performed.

Adult↗