ABSTRACT
Seventy-one 7-oxycoumarins, 66 synthesized and 5 commercially sourced, were tested for their ability to inhibit growth in murine PAM212 keratinocytes. Forty-nine compounds from the library demonstrated light-induced lethality. None was toxic in the absence of UVA light. Structure-activity correlations indicate that the ability of the compounds to inhibit cell growth was dependent not only on their physiochemical characteristics, but also on their ability to absorb UVA light. Relative lipophilicity was an important factor as was electron density in the pyrone ring. Coumarins with electron withdrawing moieties - cyano and fluoro at C3 - were considerably less active while those with bromines or iodine at that location displayed enhanced activity. Coumarins that were found to inhibit keratinocyte growth were also tested for photo-induced DNA plasmid nicking. A concentration-dependent alteration in migration on neutral gels caused by nicking was observed.
Subject(s)
Coumarins/pharmacology , Keratinocytes/drug effects , Photosensitizing Agents/pharmacology , Animals , Cell Proliferation/drug effects , Cells, Cultured , Coumarins/chemical synthesis , Coumarins/chemistry , Dose-Response Relationship, Drug , Mice , Molecular Structure , Photochemical Processes , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/chemistry , Structure-Activity RelationshipABSTRACT
Photosensitizers are used in the treatment of epidermal proliferation and differentiation disorders such as psoriasis and vitiligo. In these studies, a ring-expanded carbon homolog of the linear psoralen (furo[3,2-g]benzopyran-7-one) class of photosensitizers, 4,10-dimethyl-2H,8H-benzo[1,2-b:5,4-b']dipyran-2-one (NDH2476), was synthesized and analyzed for biological activity. Following activation by ultraviolet light (UVA, 320-400 nm), NDH2476 was found to be a potent inhibitor of keratinocyte growth (IC50 = 9 nm). Similar derivatives methylated in the pyran ring, or containing a saturated pyran ring structure, were markedly less active or inactive as photosensitizers. NDH2476 was found to intercalate and damage DNA following UVA light treatment as determined by plasmid DNA unwinding and nicking experiments. Taken together, these data demonstrate that an intact furan ring in psoralen photosensitizers is not required for keratinocyte growth inhibition or DNA damage. Our findings that low nanomolar concentrations of a benzopyranone derivative were active as a photosensitizer indicates that this or a structurally related compound may be useful in the treatment of skin diseases involving aberrant epidermal cell growth and differentiation.
Subject(s)
Keratinocytes/drug effects , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Pyranocoumarins/chemistry , Pyranocoumarins/pharmacology , Cell Proliferation/drug effects , DNA Damage , Humans , Keratinocytes/cytology , Ultraviolet RaysABSTRACT
High throughput screening of our compound library revealed a series of N-pyridyl-3-benzamides as low micromolar agonists of the human TRPV1 receptor. Synthesis of analogs in this series led to the discovery of a series of N-quinolin-3-yl-benzamides as low nanomolar antagonists of human TRPV1.
Subject(s)
Benzamides/chemical synthesis , Benzamides/pharmacology , Isoquinolines/chemistry , Pyridines/chemistry , TRPV Cation Channels/antagonists & inhibitors , TRPV Cation Channels/metabolism , Animals , Benzamides/chemistry , Benzamides/therapeutic use , Cross-Linking Reagents/chemistry , Humans , Hyperalgesia/drug therapy , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
We report on a series of alpha-substituted-beta-tetralin-derived and related phenethyl-based isoquinolinyl and hydroxynaphthyl ureas as potent antagonists of the human TRPV1 receptor. The synthesis and Structure-activity relationships (SAR) of the series are described.
Subject(s)
TRPV Cation Channels/antagonists & inhibitors , TRPV Cation Channels/metabolism , Tetrahydronaphthalenes/pharmacology , Urea/pharmacology , Binding, Competitive/drug effects , Cell Line , Drug Evaluation, Preclinical , Humans , Molecular Structure , Structure-Activity Relationship , TRPV Cation Channels/chemistry , Tetrahydronaphthalenes/chemistry , Urea/analogs & derivatives , Urea/chemistryABSTRACT
High throughput screening using the recombinant human TRPV1 receptor was used to identify a series of pyridinylpiperazine ureas (3) as TRPV1 vanilloid receptor ligands. Exploration of the structure-activity relationships by parallel synthesis identified the essential pharmacophoric elements for antagonism that permitted further optimization via targeted synthesis to provide a potent orally bioavailable and selective TRPV1 modulator 41 active in several in vivo models.
Subject(s)
Aminopyridines/chemical synthesis , Analgesics/chemical synthesis , Ion Channels/antagonists & inhibitors , Piperazines/chemical synthesis , Administration, Oral , Aminopyridines/chemistry , Aminopyridines/pharmacology , Analgesics/chemistry , Analgesics/pharmacology , Animals , Biological Availability , Body Temperature/drug effects , Calcium/metabolism , Capsaicin , Cell Line , Humans , Hypothermia/chemically induced , Hypothermia/prevention & control , Ion Channels/agonists , Male , Pain Measurement , Piperazines/chemistry , Piperazines/pharmacology , Rats , Structure-Activity Relationship , TRPV Cation ChannelsABSTRACT
Starting from a low micromolar agonist lead identified by high-throughput screening, series of N-isoquinolin-5-yl-N'-aralkyl ureas and analogous amides were developed as potent antagonists of human vanilloid receptor 1 (VR1). The synthesis and structure-activity relationships (SAR) of the series are described.
Subject(s)
Amides/chemistry , Isoquinolines/chemistry , Receptors, Drug/antagonists & inhibitors , Urea/chemistry , Amides/metabolism , Cell Line , Humans , Isoquinolines/metabolism , Receptors, Drug/metabolism , TRPV Cation Channels , Urea/metabolismABSTRACT
The design and synthesis of novel pyrrolidine-containing bradykinin antagonists, II, are described. Conformational analysis suggested that a pyrrolidine moiety could substitute for the N-methyl cis-amide moiety of FR 173657. The in vitro binding data showed that the (S)-isomer of II was potent in the bradykinin B(2) receptor-binding assay with a K(i) of 33 nM. The opposite isomer, (R)-II, had a K(i) of 46 nM. The in vitro binding data confirmed our conformational hypothesis.
Subject(s)
Bradykinin/antagonists & inhibitors , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Drug Design , Isomerism , Models, Molecular , Molecular Conformation , Receptors, Bradykinin/metabolismABSTRACT
The synthesis and structure-activity relationships of a novel series of aroylpyrrole alkylamides as potent selective bradykinin B(2) receptor antagonists are described. Several members of this series display nanomolar affinity at the B(2) receptor and show activity in an animal model of antinociception.
