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2. A-272651, a nonpeptidic blocker of large-conductance Ca2+ -activated K+ channels, modulates bladder smooth muscle contractility and neuronal action potentials

Author

Ivan Milicic, Steven A. Buckner, A Parihar, Murali Gopalakrishnan, X.-F Zhang, Sean C. Turner, J Wilkins, Char-Chang Shieh, and Jinkerson T

Subjects
Pharmacology, medicine.medical_specialty, Chemistry, Smooth muscle contraction, Iberiotoxin, Sensory neuron, Potassium channel, Contractility, Electrophysiology, medicine.anatomical_structure, Endocrinology, Internal medicine, medicine, Biophysics, Premovement neuronal activity, medicine.symptom, Muscle contraction
Abstract

Background and Purpose: The large-conductance Ca2+-activated K+ channel (BKCa, KCa1.1) links membrane excitability with intracellular Ca2+ signaling and plays important roles in smooth muscle contraction, neuronal firing, and neuroendocrine secretion. This study reports the characterization of a novel BKCa channel blocker, 2,4-dimethoxy-N-naphthalen-2-yl-benzamide (A-272651). Experimental Approach: 86Rb+ efflux in HEK-293 cells expressing BKCa was measured. Effects of A-272651 on BKCa α- and BKCa αβ1-mediated currents were evaluated by patch-clamp. Effects on contractility were assessed using low-frequency electrical field stimulated pig detrusor and spontaneously contracting guinea pig detrusor. Effects of A-272651 on neuronal activity were determined in rat small diameter dorsal root ganglia (DRG). Key Results: A-272651 (10 μM) inhibited 86Rb+ efflux evoked by NS-1608 in HEK-293 cells expressing BKCa currents. A-272651 concentration-dependently inhibited BKCa currents with IC50 values of 4.59 μM (Hill coefficient 1.04, measured at +40 mV), and 2.82 μM (Hill coefficient 0.89), respectively, for BKCa α and BKCa αβ1-mediated currents. Like iberiotoxin, A-272651 enhanced field stimulated twitch responses in pig detrusor and spontaneous contractions in guinea pig detrusor with EC50 values of 4.05±0.05 and 37.95±0.12 μM, respectively. In capsaicin-sensitive DRG neurons, application of A-272651 increased action potential firing and prolonged action potential duration. Conclusions and Implications: These data demonstrate that A-272651 modulates smooth muscle contractility and neuronal firing properties. Unlike previously reported peptide BKCa blockers, A-272651 represents one of the first small molecule BKCa channel blockers that could serve as a useful tool for further characterization of BKCa channels in physiological and pathological states. British Journal of Pharmacology (2007) 151, 798–806; doi:10.1038/sj.bjp.0707278

Published
2007
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3. Novel Transient Receptor Potential Vanilloid 1 Receptor Antagonists for the Treatment of Pain:  Structure−Activity Relationships for Ureas with Quinoline, Isoquinoline, Quinazoline, Phthalazine, Quinoxaline, and Cinnoline Moieties

Author

Gomtsyan, A., Bayburt, E. K., Schmidt, R. G., Zheng, G. Z., Perner, R. J., Didomenico, S., Koenig, J. R., Turner, S., Jinkerson, T., Drizin, I., Hannick, S. M., Macri, B. S., McDonald, H. A., Honore, P., Wismer, C. T., Marsh, K. C., Wetter, J., Stewart, K. D., Oie, T., Jarvis, M. F., Surowy, C. S., Faltynek, C. R., and Lee, C.-H.

Abstract

Novel transient receptor potential vanilloid 1 (TRPV1) receptor antagonists with various bicyclic heteroaromatic pharmacophores were synthesized, and their in vitro activity in blocking capsaicin activation of TRPV1 was assessed. On the basis of the contribution of these pharmacophores to the in vitro potency, they were ranked in the order of 5-isoquinoline > 8-quinoline = 8-quinazoline > 8-isoquinoline ≥ cinnoline ≈ phthalazine ≈ quinoxaline ≈ 5-quinoline. The 5-isoquinoline-containing compound 14a (hTRPV1 IC50 = 4 nM) exhibited 46% oral bioavailability and in vivo activity in animal models of visceral and inflammatory pain. Pharmacokinetic and pharmacological properties of 14a are substantial improvements over the profile of the high-throughput screening hit 1 (hTRPV1 IC50 = 22 nM), which was not efficacious in animal pain models and was not orally bioavailable.

Published
2005

4. In vitro structure-activity relationship and in vivo characterization of 1-(aryl)-3-(4-(amino)benzyl)urea transient receptor potential vanilloid 1 antagonists.

Author

Perner RJ, DiDomenico S, Koenig JR, Gomtsyan A, Bayburt EK, Schmidt RG, Drizin I, Zheng GZ, Turner SC, Jinkerson T, Brown BS, Keddy RG, Lukin K, McDonald HA, Honore P, Mikusa J, Marsh KC, Wetter JM, George KS, Jarvis MF, Faltynek CR, and Lee CH

Subjects
Administration, Oral, Analgesics pharmacokinetics, Analgesics pharmacology, Animals, Biological Availability, Dogs, Drug Stability, Humans, In Vitro Techniques, Indazoles pharmacokinetics, Indazoles pharmacology, Isoquinolines chemical synthesis, Isoquinolines pharmacokinetics, Isoquinolines pharmacology, Microsomes, Liver metabolism, Phenylurea Compounds pharmacokinetics, Phenylurea Compounds pharmacology, Rats, Structure-Activity Relationship, Urea chemical synthesis, Urea pharmacokinetics, Urea pharmacology, Analgesics chemical synthesis, Indazoles chemical synthesis, Phenylurea Compounds chemical synthesis, TRPV Cation Channels antagonists & inhibitors, Urea analogs & derivatives
Abstract

The synthesis and structure-activity relationship of 1-(aryl)-3-(4-(amino)benzyl)urea transient receptor potential vanilloid 1 (TRPV1) antagonists are described. A variety of cyclic amine substituents are well tolerated at the 4-position of the benzyl group on compounds containing either an isoquinoline or indazole heterocyclic core. These compounds are potent antagonists of capsaicin activation of the TRPV1 receptor in vitro. Analogues, such as compound 45, have been identified that have good in vivo activity in animal models of pain. Further optimization of 45 resulted in compound 58 with substantially improved microsome stability and oral bioavailability, as well as in vivo activity.

Published
2007
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5. Novel transient receptor potential vanilloid 1 receptor antagonists for the treatment of pain: structure-activity relationships for ureas with quinoline, isoquinoline, quinazoline, phthalazine, quinoxaline, and cinnoline moieties.

Author

Gomtsyan A, Bayburt EK, Schmidt RG, Zheng GZ, Perner RJ, Didomenico S, Koenig JR, Turner S, Jinkerson T, Drizin I, Hannick SM, Macri BS, McDonald HA, Honore P, Wismer CT, Marsh KC, Wetter J, Stewart KD, Oie T, Jarvis MF, Surowy CS, Faltynek CR, and Lee CH

Subjects
Abdominal Pain drug therapy, Administration, Oral, Analgesics chemistry, Analgesics pharmacology, Animals, Biological Availability, Calcium metabolism, Cells, Cultured, Disease Models, Animal, Heterocyclic Compounds, 2-Ring chemical synthesis, Heterocyclic Compounds, 2-Ring chemistry, Heterocyclic Compounds, 2-Ring pharmacology, Humans, Hyperalgesia drug therapy, Isoquinolines chemistry, Isoquinolines pharmacology, Models, Molecular, Quinazolines chemical synthesis, Quinazolines chemistry, Quinazolines pharmacology, Quinolines chemical synthesis, Quinolines chemistry, Quinolines pharmacology, Rats, Static Electricity, Structure-Activity Relationship, Urea chemistry, Urea pharmacology, Analgesics chemical synthesis, Isoquinolines chemical synthesis, Pain drug therapy, Receptors, Drug antagonists & inhibitors, Urea analogs & derivatives, Urea chemical synthesis
Abstract

Novel transient receptor potential vanilloid 1 (TRPV1) receptor antagonists with various bicyclic heteroaromatic pharmacophores were synthesized, and their in vitro activity in blocking capsaicin activation of TRPV1 was assessed. On the basis of the contribution of these pharmacophores to the in vitro potency, they were ranked in the order of 5-isoquinoline > 8-quinoline = 8-quinazoline > 8-isoquinoline > or = cinnoline approximately phthalazine approximately quinoxaline approximately 5-quinoline. The 5-isoquinoline-containing compound 14a (hTRPV1 IC50 = 4 nM) exhibited 46% oral bioavailability and in vivo activity in animal models of visceral and inflammatory pain. Pharmacokinetic and pharmacological properties of 14a are substantial improvements over the profile of the high-throughput screening hit 1 (hTRPV1 IC50 = 22 nM), which was not efficacious in animal pain models and was not orally bioavailable.

Published
2005
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