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1.
Molecules ; 28(3)2023 Jan 28.
Article in English | MEDLINE | ID: mdl-36770942

ABSTRACT

Positive allosteric modulators (PAMs), negative allosteric modulators (NAMs), silent agonists, allosteric activating PAMs and neutral or silent allosteric modulators are compounds capable of modulating the nicotinic receptor by interacting at allosteric modulatory sites distinct from the orthosteric sites. This survey is focused on the compounds that have been shown or have been designed to interact with nicotinic receptors as allosteric modulators of different subtypes, mainly α7 and α4ß2. Minimal chemical changes can cause a different pharmacological profile, which can then lead to the design of selective modulators. Experimental evidence supports the use of allosteric modulators as therapeutic tools for neurological and non-neurological conditions.


Subject(s)
Receptors, Nicotinic , Receptors, Nicotinic/metabolism , alpha7 Nicotinic Acetylcholine Receptor/chemistry , Allosteric Regulation , Allosteric Site
2.
Molecules ; 29(1)2023 Dec 21.
Article in English | MEDLINE | ID: mdl-38202651

ABSTRACT

The piperazine moiety is often found in drugs or in bioactive molecules. This widespread presence is due to different possible roles depending on the position in the molecule and on the therapeutic class, but it also depends on the chemical reactivity of piperazine-based synthons, which facilitate its insertion into the molecule. In this paper, we take into consideration the piperazine-containing drugs approved by the Food and Drug Administration between January 2011 and June 2023, and the synthetic methodologies used to prepare the compounds in the discovery and process chemistry are reviewed.


Subject(s)
Piperazine , United States , United States Food and Drug Administration
3.
Expert Opin Drug Discov ; 17(9): 969-984, 2022 09.
Article in English | MEDLINE | ID: mdl-35848922

ABSTRACT

INTRODUCTION: Piperazine is a structural element present in drugs belonging to various chemical classes and used for numerous different therapeutic applications; it has been considered a privileged scaffold for drug design. AREAS COVERED: The authors have searched examples of piperazine-containing compounds among drugs recently approved by the FDA and in some research fields (nicotinic receptor modulators, compounds acting against cancer, and bacterial multidrug resistance), looking in particular to the design behind the insertion of this moiety. EXPERT OPINION: Piperazine is widely used due to its peculiar characteristics, such as solubility, basicity, chemical reactivity, and conformational properties. This moiety has represented an important tool to modulate pharmacokinetic and pharmacodynamic properties of drugs.


Subject(s)
Neoplasms , Receptors, Nicotinic , Drug Design , Drug Discovery , Humans , Piperazine/pharmacology
4.
Molecules ; 27(2)2022 Jan 15.
Article in English | MEDLINE | ID: mdl-35056859

ABSTRACT

A series of histamine (HST)-related compounds were synthesized and tested for their activating properties on five physiologically relevant human Carbonic Anhydrase (hCA) isoforms (I, II, Va, VII and XIII). The imidazole ring of HST was replaced with different 5-membered heterocycles and the length of the aliphatic chain was varied. For the most interesting compounds some modifications on the terminal amino group were also performed. The most sensitive isoform to activation was hCA I (KA values in the low micromolar range), but surprisingly none of the new compounds displayed activity on hCA II. Some derivatives (1, 3a and 22) displayed an interesting selectivity for activating hCA I over hCA II, Va, VII and XIII.


Subject(s)
Carbonic Anhydrase I/metabolism , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Histamine/chemistry , Histamine/pharmacology , Carbonic Anhydrase I/drug effects , Carbonic Anhydrase II/drug effects , Carbonic Anhydrase II/metabolism , Carbonic Anhydrase V/drug effects , Carbonic Anhydrase V/metabolism , Carbonic Anhydrases/drug effects , Carbonic Anhydrases/metabolism , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Histamine/analogs & derivatives , Histamine/chemical synthesis , Humans , Imidazoles/chemistry , Protein Isoforms/drug effects , Protein Isoforms/metabolism
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