5-HT Ligand notes

5-HT1 NON-SELECTIVE

Bromocriptine - D1, 2 & HT 1, 2 Agonist RU-24,969 - Selective HT1A & B Agonist Indorenate - Anxiolytic HT Agonist 1A,B 2C

5-HT1a

This receptor is involved in neuromodulation. Agonists decrease heart rate and blood pressure, release Norepinephrine and show efficacy in anxiolysis, antidepression, analgesia and antiemetic effects, the latter two via inhibition of the NK1 receptor (Neurokinin 1). Agonism also causes serotonin modulation and vice versa; SRI's, SRA's and MOAI's activate the HT1a receptor. Dopamine release has also been found upon agonism of HT1a, contradictory to this however, agonism impairs certain aspects of memory and learning by inhibiting the release of glutamate and acetylcholine, thus some antagonists such as lecozotan have been shown to be novel treatments for Alzheimer's. Other effects of 5-HT1a activation include; Decreased aggression, Increased sociability, Decreased impulsivity, Inhibition of drug-seeking behavior, Facilitation of sex drive and arousal, Inhibition of penile erection, Diminished food intake, Prolongation of REM sleep latency and Reversal of opioid-induced respiratory depression. Has also been shown to interact with BDNF, whether increasing or decreasing it's expression within the brain.

4-Fluoro-5-MeO-DMT* - Potent HT1A agonist - (Tryptamine) 5-CT - Nonselective, high affinity full agonist at HT1A, B, D, 5A and 7 receptors, as well as at HT2, 3 and 6 with lower affinity. Negligible affinity for HT1E & 1F. It binds strongest to HT1A however. 8-OH-DPAT - HT1A, 7 agonist & SRI/RA possesses antidepressant, anxiolytic, serenic, anorectic, antiemetic and analgesic effects. Could remove muscle tension effects from psychedelics through HT7 agonim. (Aminotetraline) Alnespirone - Selective HT1A full agonist (Azapirone) Bay R 1531 - selective HT1A agonist (closed ring 5-MeO-DPT or Quartamine analogue) Bifeprunox - D2 & HT1A agonist Buspirone - HT1A, D2, 3, 4 & a1 agonist (Azapirone) CBD - Low affinity for CB1 & 2, indicating antagonistic action for other agonists. Inverse agonist of CB2, anatgonist of GPR55, HT1a agonist and allosteric modulator of u & d opioid receptros. Multiple isomers exist, possibly lowering or raising some receptor affinities. Ebalzotan - Selective HT1a agonist. Interesting structure. Eptapirone (F-11,440) - Very potent, highly selective HT1a agonist. Human trials produced at an oral dose of 1.5 mg a reduction of body temperature, suppression of REM sleep, increase in cortisol and growth hormone levels with an increase in euphoria and intoxication. Peaks within 30–60 minutes with a total duration of three hours. F-15,599 - Analogue of Eptapirone ^^ with similar affect. Ginkgo Biloba - Reversible, nonselective MAOI, Triple RI and selective HT1a agonist. Lecozotan - Competitive, selective HT1A antagonist, which enhances the Po-stimulated release of ACh and glutamate. LY-293,284* - Potent selective HT1A full agonist derived from LSD and Bay R 1531. NBUMP - Highly selective HT1A agonist over a1 & D2 receptors. Nefazodone - AD; potent HT2a antag. with low affinity for a1&2 adren., HT1a and D2. Low affinity for SERT, DAT & NET acting as weak SNDRI. Osemozotan - HT1A agonist RU-24,969 - Selective HT1A & B Agonist U-92,016-A - Potent, selective full HT1a agonist with a long duration of action. Interesting structure. Umespirone - HT1A & D2 agonist, a1 antagonist. Weak affinity for sigma receptor. (Azapirone

HT1B

In the frontal cortex it is responsible for inhibiting the release of dopamine, in the basal ganglia and striatum, 5-HT inhibits the release of serotonin and decreases glutamatergic transmission and in the Hippocampus it produces a facilitation in excitatory synaptic transmission which is altered in depression. Outside the brain, activation can cause pulmonary vasoconstriction. Knockout mice lacking the 5-HT1B gene show an increase in aggression and a higher preference for alcohol.

CP-94,253 - Potent and selective HT1b agonist. Promotes wakefulness, antidepression and enhances cocaine by increasing dopamine release. SB-216,641 - Selective HT1b antagonist, has anxiolytic properties.

HT1D

Acts on the CNS and affects locomotion and anxiety. It also induces vascular vasoconstriction in the brain.

5-(Nonyloxy)tryptamine - Selective HT1d agonist (1.0nM) BRL-15,572 - Selective HT1d antagonist useful in finding the role of HT1d. HT1d seems to modulate release of glutamate and regulates cerebral blood pressure, making agonists effective migraine cures.

HT1E

Function UNKNOWN. Hypothesised that it plays a large role in regulation of memory. This receptor is also not found in animals.

BRL-54443 - Selective agonist for HT1e & f. Only known (partially) selective ligand.

HT1F

Lasmiditan - Selective HT1f agonist used in treatment of migraines. Lack of affinity for other receptors like HT1b&d may result in fewer vasoconstriction related side effects

5-HT2

5-APB - MDA analogue. Triple RI, HT2 agonist with selectivity over 2B & C (Phenethylamine) 5-MAPB - Similar to ^^ but MDMA analogue (Phenethylamine) 6-APB - MDA analogue. Triple RI, HT2 agonist with selectivity for 2B (Phenethylamine) 6-MAPB - Similar to ^^ but MDMA analogue (Phenethylamine) Medifoxamine - DRI & HT2A & C agonist. hepatotoxic. Oxaflozane - HT1A,2A,2C Agonist Synephrine - strong a1 agonist, non selective adrenergic and HT2A

HT2A

HT2A agonism doesn't automatically mean the compound will be psychedelic. 6-Fl-DET is inactive as a psychedelic despite agonising HT2a. The same occurs in Lisuride, an ergoloid derivative. Lisuride has high affinity for D2,3&4, HT1a,2a&c but lacks psychedelic affect. This suggests that there are various genes (GPCR oligomers) encoded into the HT2a receptor and while a less selective ligand such as LSD can connect with these receptors (specifically MGluR-2), some cannot and display no psychedelic effects. This suggests that in future, compounds will be able to access these more selective sites to shape the affect of the drug.

HT2B

- CNS Presynaptic Inhibition - meaning agonism causes serotonin to be released. HT2B inhibited mice were void of MDMA-induced hyperlocomotion and 5-HT release. - Pulmonary vasoconstriction - agonism caused - HT2B regulates cardiac function. In failing human heart conditions, HT2B receptors were way overexpressed than usual. - Modulates serotonin release and protects against serotonin syndrome even if agonised.

HT2C

Significantly regulate mood, anxiety, feeding and reproducing by regulating dopamine release in multiple areas of the brain. Antagonism increases dopamine release however. Therefore the agonism of HT2C contributes to depression and anxiety. In fact suicide victims usually have an abnormally high amount of HT2C receptors present in the prefrontal cortex.

HT3

Full agonism however causes nausea and vomiting, anxiety and higher propensity of seizure rate. Similarly full antagonism causes convulsions and anxiety. Agonists also produce nociceptinergic excitation, possibly having effects of addiction and withdrawal.

RS-56812 - Potent and selective partial HT3 agonist. Memory enhancer. YM-31636 - Selective HT3 agonist, increases colonic mobility but does not induce diarrhea.

Ondanestron - Selective HT3 antagonist used as an antiemetic for cancer patients. While having no affinity for any other D or HT receptors, Ondanestron has proved useful in treating schizophrenia. It also has found use as withdrawal and craving reducer for alcohol and opioids. Thujone - Active ingredient in Absinthe. Acts as a HT3 antagonist and GABA-A antagonist, resulting in convulsions and paranoia.

HT-4

Indeloxazine* - S releaser, DRI, NMDA antag., acetylcholine releaser PRX-03140 - Partial HT4 agonist developed for Alzheimer's. RS-67,333 - Potent partial HT4 agonist as well as being a sigma-1 ligand. Possesses antidepressant and nootropic properties. SL65.0155 * - Selective partial HT4 agonist. Enhances cognition, learning, memory and has antidepressant effects. Was in phase II trials then abandoned??

HT-5a

5-HT5b is non functional in humans HT-5a functions as an agonist by negatively influencing cAMP levels via Giα & Goα receptors.

SB-699,551 - Potent and selective HT5A antagonist used to decipher the role of HT5A in humans. It seems to modulate serotonin release similar to HT1b & d.

HT-6

HT-6 blockade causes increased glutamergic and cholinergic neurotransmission, while activation enhances GABAergic signalling.

EMD-386,088 - Potent and selective HT6 agonist, however has moderate affinity for HT3. EMDT - Selective HT6 agonist. Inhibits both short and long term memory formation.

Lu AE58054 - Potent and selective HT6 antagonist, responsible for memory formation and has use for patients with Alzheimer's and schizophrenia MS-245 - Tryptamine derivative that acts as a selective HT6 antagonist. Boosts the effects of amphetamine and nicotine. PRX-07034 - Potent, selective HT6 antagonist, improving cognitive function and anoretic capabilities. SB-742,457 * - Potent, selective antagonist of HT6, with cognition, memory and learning enhancing effects. Currently under phase II trials.

5-HT7

The HT-7 receptor is coupled with the Gs proteines, stimulating cAMP levels. It also plays a role in smooth muscle relaxation within the vasculature and in the gastrointestinal tract. As a result the HT-7 receptor is involved with thermoregulation, circadian rhythm, learning and memory, sleep and mood regulation.

AS-19 - potent HT7 agonist associated with long term memory. Revereses amnesia induced by drugs such as scopolamine and dizocilpine and improves long term memory acquisition, but inhibits short term memory formation. E-55888 - Potent, selective HT7 agonist, when administered alongside morphine it was found to significantly increase analgesic effects N-Methylserotonin - Selective and high affinity HT1a & 7 agonist, while also functioning as an SSRI. RA-7** - 1-(2-Diphenyl)piperazine. Potent and selective HT7 agonist. Similar in struture to such compounds as 2-DPMP and PCP.

SB-258,719 - Potent, selective HT7 antagonist (or Inverse agonist). Potential for use as an analgesic but also include treatment for anxiety, depression and usage as a nootropic.

NON-SELECTIVE

CSP-2503 * - Potent and Selective HT1a agonist, HT2a and HT3 antagonist. Produces anxiolytic effects and potential substance addiction cure. EGIS-12,233 - Potent and selective HT6&7 antagonist, increases dopamine within cochlear tissue indicating a role in regulation of the hearing system. TFMPP - Full agonist at HT1a, b, d and 2c, partial agonist or antagonist at 2a. Also binds to SERT and evokoes the release of serotonin. Adatanserin - Mixed HT1a partial agonist and HT2a & c antagonist. Neuroprotective against ischemia-induced glutamatergic excitotoxicity. (Ischemia = restriction of blood supply to tissues)