- Design, Synthesis, and Pharmacological Characterization of Heterobivalent Ligands for the Putative 5-HT2A/mGlu2Receptor Complex
-
We report the synthesis of the first series of heterobivalent ligands targeting the putative heteromeric 5-HT2A/mGlu2 receptor complex, based on the 5-HT2A antagonist MDL-100,907 and the mGlu2 ago-PAM JNJ-42491293. The functional properties of monovalent and heterobivalent ligands were characterized in 5-HT2A-, mGlu2/Gqo5-, 5-HT2A/mGlu2-, and 5-HT2A/mGlu2/Gqo5-expressing HEK293 cells using a Ca2+ imaging assay and a [3H]ketanserin binding assay. Pronounced functional crosstalk was observed between the two receptors in 5-HT2A/mGlu2 and 5-HT2A/mGlu2/Gqo5 cells. While the synthesized monovalent ligands retained the 5-HT2A antagonist and mGlu2 ago-PAM functionalities, the seven bivalent ligands inhibited 5-HT-induced responses in 5-HT2A/mGlu2 cells and both 5-HT- and Glu-induced responses in 5-HT2A/mGlu2/Gqo5 cells. However, no definitive correlation between the functional potency and spacer length of the ligands was observed, an observation substantiated by the binding affinities exhibited by the compounds in 5-HT2A, 5-HT2A/mGlu2, and 5-HT2A/mGlu2/Gqo5 cells. In conclusion, while functional crosstalk between 5-HT2A and mGlu2 was demonstrated, it remains unclear how these heterobivalent ligands interact with the putative receptor complex.
- Poulie, Christian B. M.,Liu, Na,Jensen, Anders A.,Bunch, Lennart
-
p. 9928 - 9949
(2020/09/12)
-
- 20-HETE FORMATION INHIBITORS
-
This disclosure provides novel heterocyclic compounds and methods for inhibiting the enzyme CYP4. Further disclosed methods include: a method of inhibiting the biosynthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) in a subject in need thereof and a method of producing neuroprotection and decreased brain damage by preventing cerebral microvascular blood flow impairment and anti-oxidant mechanisms in a subject experiencing or having experienced an ischemic event.
- -
-
Paragraph 0357-0360; 0371; 0372
(2020/08/23)
-
- Design, syntheses, and characterization of pharmacophore based chemokine receptor CCR5 antagonists as anti prostate cancer agents
-
Accumulating evidence has shown multiple roles that chemokine receptor CCR5 may play to promote the progression of several types of cancer. The mechanism of such promotion is believed to involve chronic inflammation that creates a microenvironment which e
- Arnatt, Christopher K.,Zaidi, Saheem A.,Zhang, Zhu,Li, Guo,Richardson, Amanda C.,Ware, Joy L.,Zhang, Yan
-
p. 647 - 658
(2013/10/22)
-
- A versatile synthesis of 4-aryl tetrahydropyridines via palladium mediated Suzuki cross-coupling with cyclic vinyl boronates
-
A simple preparation of cyclic vinyl boronates derived from the vinyl triflates of N-protected tetrahydropyridines is described. Suzuki coupling of the boronates with aryl bromides, iodides and triflates proceeds in good yield to give 4-aryl tetrahydropyridines. (C) 2000 Elsevier Science Ltd.
- Eastwood, Paul R.
-
p. 3705 - 3708
(2007/10/03)
-
- Heterocyclic compounds for the treatment of CNS and cardiovascular disorders
-
Novel aromatic bicyclic amines of formula (I) STR1 are useful in treating central nervous system disorders and cardiac arrhythmias and cardiac fibrillation.
- -
-
-
- Aryl substituted heterocycles
-
The present invention concerns the novel use of aryl substituted heterocycles of formula I, set out below, which antagonize the pharmacological actions of one of ent endogenous neuropeptide tachykinins an the neurokinin 2 (NK2) receptor making them useful whenever such antagonism is desired, such as in the treatment of asthma and related conditions. The invention also provides pharmaceutical compositions containing the aryl substituted heterocycles for use in such treatment. Certain novel aryl substituted heterocycles of formula I and novel intermediates for their manufacture are also provided. STR1
- -
-
-
- Aromatically substituted azacycloalkyl-alkanediphosphonic acids useful for the treatment of illnesses that can be attributed to calcium metabolism disorders
-
Aromatically substituted azacycloalkylalkanediphosphonic acids of the formula STR1 in which R represents an aromatically substituted azacycloaliphatyl radical that is bonded to the group alk by way of a nitrogen atom and that optionally contains an additional nitrogen atom, and alk represents a divalent aliphatic radical, and their salts, can be used for the treatment of illnesses that can be attributed to calcium metabolism disorders. They are manufactured, for example, by reacting a compound of the formula in which X3 represents carboxy, carbamoyl or cyano, with phosphorus acid and phosphorus trichloride and in an intermediate of the formula STR2 obtained by starting from compounds of the formula IV in which X3 represents cyano or carbamoyl and by working up by hydrolysis, or in a salt thereof, replacing the amino group by hydroxy by treatment with nitrous acid.
- -
-
-