5-Alkyltryptamine derivatives as highly selective and potent 5-HT1D receptor agonists

A series of 5-alkyltryptamines (6) and the corresponding conformationally constrained analogues (8) have been synthesized. The structure activity relationships (SAR) at the 5-position of the indole skeleton and the ethylamine side chain have been studied. Functional activities were assessed using isolated rabbit saphenous vein. Potent, selective ligands were found (6e, Ki 2.5 nM, 5-HT1B/5-HT1D 125-fold) that have potential for treating acute migraine.     

New piperidinyl- and 1,2,3,6-tetrahydropyridinyl-pyrimidine derivatives as selective 5-HT1A receptor agonists with highly potent anti-ischemic effects

A series of new piperidinyl- and 1,2,3,6-tetrahydropyridinyl-pyrimidine derivatives were synthesized. Among these compounds, 4-methyl-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine derivative 23 (SUN N5147) exhibited sub-nanomolar affinity for 5-HT1A receptor with 1000-fold selectivity over both dopamine D2 and alpha1-adrenergic receptors and remarkable neuroprotective activity in a transient middle cerebral artery occlusion (t-MCAO) model.     

Effects of 5-HT1A receptor agonist and antagonist on anxiety in intact and ovariectomized female rats

The purpose of this work was to study the role of 5-HT1A receptors on the level of anxiety in adult intact and ovariectomized (OVX) female rats. The influence of chronic administration of 5-HT1A receptor agonist 8-OH-DPAT (0.05 mg/kg, s.c.) and 5-HT1A receptor antagonist NAN-190 (0.1 mg/kg, i.p.) given for 14 days alone or in combination with 17beta-estradiol (0.5 microg i.m./rat/day) was studied on behavior in the elevated plus maze. In intact females administration of NAN-190 resulted in significant increase in the number of enterings and the time spent on the open arms in every phase of the estrous cycle, however, 8-OH-DPAT failed to modify these parameters. In OVX females 8-OH-DPAT alone or in combination with 17beta-estradiol significantly increased the number of enterings and time spent on the open arms. On the contrary, NAN-190 alone or in combination with 17beta-estradiol in OVX females failed to evoke behavioral changes in the elevated plus maze. Thus, the 5-HT1A receptor antagonist NAN-190 induced anxiolytic effect in intact female rats, while 5-HT1A receptor agonist 8-OH-DPAT produced an anxiolytic profile on OVX rats. Results of this work specify the involvement of 5-HT1A receptors in behavioral mechanisms of anxiety in OVX female rats.     

New 5-HT1A receptor agonists possessing 1,4-benzoxazepine scaffold exhibit highly potent anti-ischemic effects

A series of new 3-substituted-4-(4-aminobutyl)-1,4-benzoxazepin-5(4H)-one derivatives (1-5) which showed a very high affinity for 5-HT1A receptor with good selectivity over dopamine D2 receptor was synthesized. Among these compounds, 3-chloro-4-[4-[4-(2-pyridinyl)-1,2,3,6-tetrahydropyridin-1-yl]butyl]-1,4-benzoxazepin-5(4H)-one (5: SUN N4057) exhibited remarkable neuroprotective activity in a transient middle cerebral artery occlusion (t-MCAO) model.     

Identification of serotonin 5-HT1A receptor partial agonists in ginger

Animal studies suggest that ginger (Zingiber officinale Roscoe) reduces anxiety. In this study, bioactivity-guided fractionation of a ginger extract identified nine compounds that interact with the human serotonin 5-HT_1A receptor with significant to moderate binding affinities (K_i = 3–20 μΜ). [³⁵S]-GTPγS assays indicated that 10-shogaol, 1-dehydro-6-gingerdione, and particularly the whole lipophilic ginger extract (K_i = 11.6 μg/ml) partially activate the 5-HT_1A receptor (20–60% of maximal activation). In addition, the intestinal absorption of gingerols and shogaols was simulated and their interactions with P-glycoprotein were measured, suggesting a favourable pharmacokinetic profile for the 5-HT_1A active compounds.     

Effects of novel 5-HT1A receptor antagonists on measures of postsynaptic 5-HT1A receptor activation in vivo

The effects of two putative 5-HT_1A antagonists, 4-(2′-methoxyphenyl)-1-[2′-[N-(2″-pyridinyl)-p-iodobenzamido]ethyl]piperazine (p-MPPI) and 4-(2′-methoxyphenyl)-1-[2′-[N-(2″-pyridinyl)-p-flourobenzamido]ethyl]piperazine (p-MPPF), were examined in vivo in two tests of postsynaptic 5-HT_1A receptor activation, hypothermia and reciprocal forepaw treading, in the rat. Both p-MPPI (10 mg/Kg, I.p.) and p-MPPF (10 mg/Kg, I.p.) antagonized the hypothermia induced by the 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.5 mg/Kg, S.c.). Neither p-MPPI nor p-MPPF administered alone at a dose of 10 mg/kg (i.p.) induced hypothermia. Similarly, both p-MPPI (10 mg/Kg, I.p.) and p-MPPF (2.5 mg/Kg, I.p.) completely antagonized 8-OH-DPAT (2 mg/Kg, S.c.)-induced forepaw treading in rats pretreated with reserpine (1 mg/Kg, S.c., 18–24 hours prior to the experiment). p-MPPI and p-MPPF, at doses of 10 mg/kg (i.p.) did not induce forepaw treading in reserpine pretreated animals. The results of the present study demonstrate that p-MPPI and p-MPPF act as 5-HT_1A receptor antagonists in these measures of postsynaptic 5-HT_1A a receptor activation.     

Discovery of a new series of 5-HT1A receptor agonists

Starting from compounds previously identified as α₁-adrenoceptor antagonists that were also found to bind to the 5-HT_1A receptor, in an attempt to separate the two activities, a new series of 5-HT_1A receptor agonists was identified and shown to have high potency and/or high selectivity. Of these, compound 13, which combines high selectivity (5-HT_1A/α₁ = 151) and good agonist potency (pD₂ = 7.82; E_max = 76), was found to be the most interesting.     

Synthesis and SAR of potent and selective tetrahydropyrazinoisoquinolinone 5-HT2C receptor agonists

The 5-HT_2C receptor has been implicated as a critical regulator of appetite. Small molecule activation of the 5-HT_2C receptor has been shown to affect food intake and regulate body weight gain in rodent models and more recently in human clinical trials. Therefore, 5-HT_2C is a well validated target for anti-obesity therapy. The synthesis and structure–activity relationships of a series of novel tetrahydropyrazinoisoquinolinone 5-HT_2C receptor agonists are presented. Several members of this series were identified as potent 5-HT_2C receptor agonists with high functional selectivity against the 5-HT_2A and 5-HT_2B receptors and reduced food intake in an acute rat feeding model upon oral dosing.     

Attempts to reinstate lordosis reflex in estrogen-primed spinal female rats with monoamine agonists

Female rats with complete transections of spinal cord at low thoracic levels did not perform lordosis. After treatment with quipazine, a serotonin receptor stimulant, some spinal rats were able to show hindquarter responses which resembled parts of the lordosis reflex. Also, serotonin receptor stimulants increased the intensity and receptive field size of vertebral dorsiflexion, a component of lordosis, in spinal females.     

5-HT1A受体阻断剂对乙醇引起大鼠低体温和行为性体温调节反应的影响

目的：观察5-羟色胺1A （5-HT_1A）受体阻断剂p-MPPI对乙醇引起大鼠低体温和行为性体温调节反应的影响。方法：用无线遥控测温技术记录成年雄性SD大鼠体核温度和活动的变化。用无线遥测温度梯度仪监测大鼠体核温度和行为性体温调节活动,将大鼠置于15℃~40℃的温度梯度箱内,并允许动物自由选择箱内温度,观察乙醇（3 g/kg）引起低体温和行为性体温调节的反应以及5-HT_1A受体阻断剂p-MPPI （1 mg/kg）对其效应的影响。结果：①乙醇能引起大鼠快速的体温降低反应,同时动物选择较低的环境温度。②5-HT_1A受体阻断剂p-MPPI能明显阻断乙醇引起的低体温和行为性体温调节变化。结论：①乙醇能使体温调定点降低,因为乙醇引起低体温时,大鼠选择较冷环境温度区;②5-HT可能参与乙醇引起低体温与行为性体温调节活动。     

N-[[1-(2-phenylethyl)pyrrolidin-2-yl]methyl]cyclohexanecarboxamides as selective 5-HT1A receptor agonists

A series of benzamides was synthesized as selective agonists for the 5-HT1A receptor. It was found that (S)-N-[[1-(2-phenylethyl)pyrrolidin-2-yl]methyl]cyclohexanecarb oxamide(7-(S)) has potent and selective agonistic activity for the 5-HT1A receptor (5-HT1A; Ki 0.49 nmol/L, D2; IC50 = >1000 nmol/L, 5-HT2; Ki = 240 nmol/L).     

Synthesis and pharmacological evaluation of benzamide derivatives as selective 5-HT(4) receptor agonists

It is thought that selective 5-HT(4) receptor agonists-such as 4-amino-5-chloro-2-methoxy-N-[1-(6-oxo-6-phenylhexyl)piperidin-4ylmethyl]benzamide (2)-have the ability to enhance both upper and lower gastrointestinal motility without any significant adverse effects. Modification of 2 was performed. Variation of the piperidin-4ylmethyl moiety of 2 led to a decrease in the binding affinity for the 5-HT(4) receptor. Following conversion of the carbonyl group on the benzoyl part to a hydroxyl or sulfoxide group, the binding affinity for the 5-HT(4) receptor was retained although the effect on defecation was reduced. Many of the 4-amino-5-chloro-2-methoxy-N-(piperidin-4ylmethyl)benzamides that had a ether or sulfide moiety in the side-chain part at the 1-position of the piperidine exhibited high affinity for the 5-HT(4) receptor. Among these, phenylthio 41c and benzylthio derivative 44 were selective 5-HT(4) receptor agonists, and had a similar effect on defecation to compound 2.     

A novel fluorinated tryptamine with highly potent serotonin 5-HT1A receptor agonist properties

Synthesis and biological evaluation of a novel fluorinated tryptamine analogue are described. This new compound 1-(4-fluoro-5-methoxyindol-3-yl)pyrrolidine (2) was found to be a potent serotonin 5-HT1A agonist.     

Effects of voluntary and forced exercise on lordosis behavior in female rats

We measured sexual behavior (lordosis) in ovariectomized, steroid-treated, exercising female rats. When estradiol-treated animals exercised voluntarily, lordosis was directly related to the amount of exercise. Forced exercise (swimming) following treatment with estradiol 17 beta and progesterone significantly increased lordosis scores but only after animals swam for 2.5 hr per day. Lordosis behavior returned to baseline levels 7 weeks after forced exercise was stopped. Circulating levels of estrogen and progesterone measured immediately after behavioral testing did not differ between animals forced to exercise and their controls. The mechanisms responsible for the increase in lordosis behavior following exercise are unclear. It is possible that a change in body composition, a change in neural sensitivity to gonadal steroids, and/or changes in pituitary or adrenal function contribute to the increased lordosis behavior in exercised animals.     

Effects of 5-HT1A and 5-HT2A receptor stimulation on temporal differentiation performance in the fixed-interval peak procedure

We examined the effects of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 5-HT(2A/2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) on performance on the fixed-interval peak procedure, and the sensitivity of these effects to 5-HT1A and 5-HT2A receptor antagonists (N-[2-(4-[2-methoxyphenyl]-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide [WAY-100635] and ketanserin). Rats were trained to press a lever for food reinforcement in 50 min sessions consisting of 32 trials in which the lever was continuously available, separated by 10 s inter-trial intervals. In 16 trials, reinforcement was delivered following the first response after 30 s had elapsed since trial onset (fixed-interval 30 s). In 16 randomly interposed (peak/probe) trials, reinforcement was omitted, and the lever remained in the operant chamber for 120 s. Response rate in probe trials was plotted against time from trial onset. Time to peak response rate (t(peak)) and the Weber fraction were derived from modified Gaussian curves fitted to each rat's data. 8-OH-DPAT (0.05 mg kg(-1)) reduced t(peak) and increased the Weber fraction; the effect on t(peak) was antagonized by WAY-100635 (0.1 mg kg(-1)). DOI (0.25 mg kg(-1)) also reduced t(peak) and increased the Weber fraction; the reduction of t(peak) was antagonized by ketanserin (2 mg kg(-1)). Stimulation of 5-HT1A and 5-HT2A receptors alters temporal differentiation in qualitatively similar ways.     

New potent and selective A1 adenosine receptor agonists

Thiirane analogs of ENAdo have been synthesised and found to be extremely potent and selective A(1) adenosine receptor agonists.     

A 5-HT4 receptor transmembrane network implicated in the activity of inverse agonists but not agonists

Activation of G protein-coupled receptors is thought to involve disruption of intramolecular interactions that stabilize their inactive conformation. Such disruptions are induced by agonists or by constitutively active mutations. In the present study, novel potent inverse agonists are described to inhibit the constitutive activity of 5-HT(4) receptors. Using these compounds and specific receptor mutations, we investigated the mechanisms by which inverse agonists may reverse the disruption of intramolecular interactions that causes constitutive activation. Two mutations (D100(3.32)A in transmembrane domain (TMD)-III and F275(6.51)A in TMD-VI) were found to completely block inverse agonist effects without impairing their binding properties nor the molecular activation switches induced by agonists. Based on the rhodopsin model, we propose that these mutated receptors are in equilibrium between two states R and R* but are unable to reach a third "silent" state stabilized by inverse agonists. We also found another mutation in TMD-VI (W272(6.48)A) that stabilized this silent state. This mutant remained fully activated by agonists. Molecular modeling indicated that Asp-100, Phe-275, and Trp-272 might constitute a network required for stabilization of the silent state by the described inverse agonists. However, this network is not necessary for agonist activity.     

Identification of a potent and selective 5-HT1B receptor antagonist

An SAR study around the mixed 5-HT1ABD receptor antagonist SB-272183 found that introduction of cis-2,6-dimethyl substitution onto the piperazine ring was a key structural change, which imparted a combination of both excellent selectivity over the 5-HT1A and 5-HT1D receptors and low intrinsic activity. This led to the identification of the selective 5-HT1B receptor antagonist SB-616234.     

Synthesis of potent and selective serotonin 5-HT1B receptor ligands

A series of serotonin 5-HT1B ligands were synthesized and evaluated for their potency and selectivity against other 5-HT receptor subtypes. Many of these new compounds displayed high affinity and selectivity for the 5-HT1B receptor and compound 6c was found to have the in vitro binding profile necessary for development as a PET radioligand.