SB-271,046
Encyclopedia
SB-271,046 is a drug which is used in scientific research. It was one of the first selective 5-HT6
receptor
antagonists to be discovered, and was found through high-throughput screening
of the SmithKline Beecham Compound Bank using cloned 5-HT6 receptors as a target, with an initial lead compound being developed into SB-271,046 through a structure-activity relationship
(SAR) study. SB-271,046 was found to be potent and selective in vitro
and had good oral bioavailability in vivo
, but had poor penetration across the blood-brain barrier
, so further SAR work was then conducted, which led to improved 5-HT6 antagonists such as SB-357,134
and SB-399,885
.
SB-271,046 was found to increase levels of the excitatory amino acid
neurotransmitter
s glutamate and aspartate, as well as dopamine
and noradrenaline in the frontal cortex and hippocampus
of rats, and 5-HT6 antagonists have been shown to produce nootropic
effects in a variety of animal studies. Suggested applications of these drugs include treatment of schizophrenia
and other psychiatric disorders.
5-HT6 receptor
The 5-HT6 receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gs/Go and mediates excitatory neurotransmission. HTR6 denotes the human gene encoding for the receptor.-Distribution:The 5-HT6 receptor is...
receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
antagonists to be discovered, and was found through high-throughput screening
High-throughput screening
High-throughput screening is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry. Using robotics, data processing and control software, liquid handling devices, and sensitive detectors, High-Throughput Screening allows a...
of the SmithKline Beecham Compound Bank using cloned 5-HT6 receptors as a target, with an initial lead compound being developed into SB-271,046 through a structure-activity relationship
Structure-activity relationship
The structure–activity relationship is the relationship between the chemical or 3D structure of a molecule and its biological activity. The analysis of SAR enables the determination of the chemical groups responsible for evoking a target biological effect in the organism...
(SAR) study. SB-271,046 was found to be potent and selective in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
and had good oral bioavailability in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
, but had poor penetration across the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
, so further SAR work was then conducted, which led to improved 5-HT6 antagonists such as SB-357,134
SB-357,134
SB-357,134 is a drug which is used in scientific research. It acts as a potent, selective and orally active 5-HT6 receptor antagonist. SB-357,134 and other 5-HT6 antagonists show nootropic effects in animal studies, and have been proposed as potential novel treatments for cognitive disorders such...
and SB-399,885
SB-399,885
SB-399885 is a drug which is used in scientific research. It acts as a potent, selective and orally active 5-HT6 receptor antagonist, with a Ki of 9.0nM...
.
SB-271,046 was found to increase levels of the excitatory amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s glutamate and aspartate, as well as dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
and noradrenaline in the frontal cortex and hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
of rats, and 5-HT6 antagonists have been shown to produce nootropic
Nootropic
Nootropics , also referred to as smart drugs, brain steroids, memory enhancers, cognitive enhancers, and intelligence enhancers, are drugs, supplements, nutraceuticals, and functional foods that improve mental functions such as cognition, memory, intelligence, motivation, attention, and concentration...
effects in a variety of animal studies. Suggested applications of these drugs include treatment of schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
and other psychiatric disorders.