Histamine is a chemical messenger involved in a number of physiological processes; it triggers its pharmacological actions through three receptor subtypes: the postsynaptic H1, H2 and the presynaptic H3. The first two are well known as they are involved respectively in allergic and inflammatory responses and in gastric acid secretion, while the third one was discovered more recently, namely in 1983 by Arrang, Garbarg and Schwartz. The H3 receptors are chiefly localized in the CNS, where they act as inhibitory autoreceptors in the central histaminergic neuronal pathways. Later studies provided evidence for their role as inhibitory heteroreceptors in nerve terminals of noradrenergic, serotoninergic, dopaminergic and peptidergic neurons. At a lesser extent they can be found in periphery too, particularly in sympathetic, parasympathetic and NANC nerve endings in gastrointestinal, respiratory and cardiovascular tissues. The widespread diffusion of H3 receptors in many brain regions suggests the involvement of histamine in memory and learning processes, in several emotional and motory functions, in the modulation of sleep-wake behaviour and awakening; also body temperature, hunger, thirst and power of concentration are brain functions likely to be regulated by H3-receptors. Thus, H3-antagonists could be potentially employed against a variety of CNS disorders, such as schizophrenia, narcolepsy, epilepsy, ADHD, Alzheimer’s disease and obesity. Nitric oxide (NO), a recently discovered endogenous messenger, displays a variety of actions in the human body. In CNS it is released from neurons following stimulation of excitatory N-methyl-D-aspartate (NMDA) receptors, it diffuses in adjacent presynaptic nerve terminals and astrocytes where it activates soluble guanylate cyclase (sGC): this results in a cascade of events, including formation of memory and control of food intake. Peripherically nitric oxide has a well-recognised role in cardiovascular, nervous and immune systems, where it elicits a wide range of physiological and patophysiological effects. Nowadays there is a great interest in hybrid drugs which combine NO-donor moieties with appropriate pharmacophoric groups; in the light of literature data mentioned above, and taking into account our experience in this field of research, we decided to design molecular hybrids endowed with mixed H3-antagonistic-NO-donor properties. The general structure of typical imidazole-type H3-antagonists is constituted by three chains (A-C). Chain A is usually a short methylene chain (3-5 terms), and optimum activity is achieved with 3 carbon atoms. The polar group can be very different in its nature: guanidine, amidine, amine, ether, urea, thiourea, oxadiazole and many other functionalities have been employed in designing selective H3-antagonists; this part of the molecule is thought to be responsible for the affinity to H3 receptors, thus constituting the pharmacophoric pattern. The lipophilic residue connected to the pharmacophore through chain B usually modulates the potency of the antagonist. We developed a first series of hybrids based on the lead structure of SKF 91486, because it guaranteed good opportunities of modulation without losing affinity for H3 receptors. SKF 91486 was coupled, through appropriate spacers, with 3-phenylfuroxan-4-yloxy and 3-benzenesulphonylfuroxan-4-yloxy moieties. Our research group has been employing for several years the furoxan nucleus (1,2,5-oxadiazole 2-oxide) as, unlike most NO-donor functionalities, it allows to modulate rate and amount of nitric oxide release by changing the substituents on the ring. Encouraged by the positive results achieved, we developed another series of antagonists based on the lead structure of ciproxifan, where the guanidine group was replaced by a simple ethereal or thioethereal bridge, in an effort to get simpler and less hydrophilic molecules more suitable for CNS penetration. This time, in addition to furoxan nuclei, we decided to couple the pharmacophore also with a nitric ester function. Besides NO-releasing molecules, we realised also derivatives devoid of NO-donor properties, in order to assay pure H3-antagonists vs the molecular hybrids: for this purpose, furoxans were replaced by furazans, and the dinitrate was assayed vs the allylic homologue. NO release was determined in vitro by spectrophotometrical detection of nitrites, which are the main product deriving from aerobic oxidation of nitric oxide. The H3 receptor antagonism was evaluated by measuring the ability of each compound to inhibit the concentration-dependent inhibitory effect of (R)-α-methylhistamine on electrically-evoked contractions of guinea pig ileum. All compound were also assayed on guinea pig papillary muscle to determine their ability to stimulate H2 receptors.
H3-Receptor Antagonists Endowed with NO-Donor Properties
TOSCO, Paolo
2002-01-01
Abstract
Histamine is a chemical messenger involved in a number of physiological processes; it triggers its pharmacological actions through three receptor subtypes: the postsynaptic H1, H2 and the presynaptic H3. The first two are well known as they are involved respectively in allergic and inflammatory responses and in gastric acid secretion, while the third one was discovered more recently, namely in 1983 by Arrang, Garbarg and Schwartz. The H3 receptors are chiefly localized in the CNS, where they act as inhibitory autoreceptors in the central histaminergic neuronal pathways. Later studies provided evidence for their role as inhibitory heteroreceptors in nerve terminals of noradrenergic, serotoninergic, dopaminergic and peptidergic neurons. At a lesser extent they can be found in periphery too, particularly in sympathetic, parasympathetic and NANC nerve endings in gastrointestinal, respiratory and cardiovascular tissues. The widespread diffusion of H3 receptors in many brain regions suggests the involvement of histamine in memory and learning processes, in several emotional and motory functions, in the modulation of sleep-wake behaviour and awakening; also body temperature, hunger, thirst and power of concentration are brain functions likely to be regulated by H3-receptors. Thus, H3-antagonists could be potentially employed against a variety of CNS disorders, such as schizophrenia, narcolepsy, epilepsy, ADHD, Alzheimer’s disease and obesity. Nitric oxide (NO), a recently discovered endogenous messenger, displays a variety of actions in the human body. In CNS it is released from neurons following stimulation of excitatory N-methyl-D-aspartate (NMDA) receptors, it diffuses in adjacent presynaptic nerve terminals and astrocytes where it activates soluble guanylate cyclase (sGC): this results in a cascade of events, including formation of memory and control of food intake. Peripherically nitric oxide has a well-recognised role in cardiovascular, nervous and immune systems, where it elicits a wide range of physiological and patophysiological effects. Nowadays there is a great interest in hybrid drugs which combine NO-donor moieties with appropriate pharmacophoric groups; in the light of literature data mentioned above, and taking into account our experience in this field of research, we decided to design molecular hybrids endowed with mixed H3-antagonistic-NO-donor properties. The general structure of typical imidazole-type H3-antagonists is constituted by three chains (A-C). Chain A is usually a short methylene chain (3-5 terms), and optimum activity is achieved with 3 carbon atoms. The polar group can be very different in its nature: guanidine, amidine, amine, ether, urea, thiourea, oxadiazole and many other functionalities have been employed in designing selective H3-antagonists; this part of the molecule is thought to be responsible for the affinity to H3 receptors, thus constituting the pharmacophoric pattern. The lipophilic residue connected to the pharmacophore through chain B usually modulates the potency of the antagonist. We developed a first series of hybrids based on the lead structure of SKF 91486, because it guaranteed good opportunities of modulation without losing affinity for H3 receptors. SKF 91486 was coupled, through appropriate spacers, with 3-phenylfuroxan-4-yloxy and 3-benzenesulphonylfuroxan-4-yloxy moieties. Our research group has been employing for several years the furoxan nucleus (1,2,5-oxadiazole 2-oxide) as, unlike most NO-donor functionalities, it allows to modulate rate and amount of nitric oxide release by changing the substituents on the ring. Encouraged by the positive results achieved, we developed another series of antagonists based on the lead structure of ciproxifan, where the guanidine group was replaced by a simple ethereal or thioethereal bridge, in an effort to get simpler and less hydrophilic molecules more suitable for CNS penetration. This time, in addition to furoxan nuclei, we decided to couple the pharmacophore also with a nitric ester function. Besides NO-releasing molecules, we realised also derivatives devoid of NO-donor properties, in order to assay pure H3-antagonists vs the molecular hybrids: for this purpose, furoxans were replaced by furazans, and the dinitrate was assayed vs the allylic homologue. NO release was determined in vitro by spectrophotometrical detection of nitrites, which are the main product deriving from aerobic oxidation of nitric oxide. The H3 receptor antagonism was evaluated by measuring the ability of each compound to inhibit the concentration-dependent inhibitory effect of (R)-α-methylhistamine on electrically-evoked contractions of guinea pig ileum. All compound were also assayed on guinea pig papillary muscle to determine their ability to stimulate H2 receptors.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
