Rosmanol is a natural polyphenol from the herb rosemary (Rosmarinus officinalis L.) with high antioxidant activity. Rosmanol markedly inhibited LPS-stimulated iNOS and COX-2 protein and gene expression, as well as the downstream products, NO and PGE2 in RAW 264.7 cells. Treatment with Rosmanol also reduced translocation of the nuclear factor-κB (NF-κB) subunits by prevention of the degradation and phosphorylation of inhibitor κB (IκB). Rosmanol exerted significant antinociceptive effects in both hot plate and tail immersion tests at the dose level of 10-100 mg/kg. The cellular and neural mechanisms underlying pain responses elicited involve interplay of a number of neurotransmitters and ion channel, and the central analgesic effects of Rosmanol were not antagonized by the opioid receptor antagonist naloxone. This indicates that the central analgesic effects of Rosmanol may be exerted via one or more of several proposed nonopioid mechanisms such as blockade of voltage-gated Na+ channels, activation of the noradrenergic inhibitory system, enhancement of GABAergic and/or serotonergic systems. The physiological and toxicological properties of this compound have not been evaluated in humans.

BIO-5192 is a highly selective and potent (KD of <10 pM) inhibitor of integrin alpha 4 beta 1. The high affinity for integrin alpha 4 beta 1 results from an extremely slow dissociation rate of the inhibitor from the integrin/inhibitor complex, with a dissociation half-life of >12 h for both the unactivated and activated integrin. Preclinical trials in multiple sclerosis in USA were underway, but no recent development of BIO-5192 or its pegylated form has been reported; it appears that development has been discontinued.

BIIE-0246 is a highly potent, high affinity antagonist selective for the Y2 receptor subtype. BIIE-0246 is a drug used in scientific research, it was one of the first non-peptide Y2-selective antagonists developed, and remains among the most widely used tools for studying this receptor. It has been used to demonstrate a role for the Y2 subtype as a presynaptic autoreceptor limiting further neuropeptide Y release, as well as modulating dopamine and acetylcholine release. Blockade of central neuropeptide Y (NPY) Y2 receptors by BIIE-0246 has being shown to reduce ethanol self-administration in rats.

BIBO-3304 is a subtype selective nonpeptide antagonist with subnanomolar affinity for the Y1 receptor subtype that significantly inhibits food intake induced by application of NPY or by fasting. BIBO-3304 is a NPY Y1 receptor antagonist (IC50 values are 0.38 and 0.72 nM at human and rat receptors respectively) that displays > 2600-fold selectivity over Y2, Y4 and Y5 receptors.

2,5-Dimethoxy-4-trifluoromethylamphetamine (DOTFM) is the alpha-methylated analogue of 2C-TFM, a psychedelic drug of the phenethylamine and amphetamine chemical classes. 2,5-Dimethoxy-4-trifluoromethylamphetamine acts as an nanomolar agonist at the 5HT2A and 5HT2C receptors and possess hallucinogenic effects in humans.

CGP-71683A is a non-peptidic neuropeptide Y (NPY) Y5 receptor antagonist that was under development by Novartis. CGP-71683A is an extremely selective, non-peptide NPY Y5 receptor antagonist, displaying > 1000-fold selectivity over Y1, Y2 and Y4 receptors; IC50 values are 1.4, 2765, 7187 and 5637 nM at cloned rat Y5, Y1, Y2 and Y4 receptors respectively. CGP-71683A potently inhibits NPY-induced food intake following i.p. administration in diabetic, free-feeding and fasted rats.

Idazoxan is an alpha2 receptor antagonist which also shows activity at imidazoline I1 and I2 receptors and modulates the release of dopamine. Idazoxan was in phase II development in the US. Later the development of idazoxan for schizophrenia was discontinued. It was also in clinical trials for cognition disorders in United Kingdom, and was also discontinued. Idazoxan is used in scientific research as a tool for the study of alpha 2-adrenoceptors. Idazoxan`s diastereoisomers possess different relative selectivity for alpha2- pre- and postsynaptic receptors: ( )-idazoxan was 7-8 times more potent than (-)-idazoxan in inhibiting p-[3H]aminoclonidine binding, and 40 times more active in antagonizing clonidine at presynaptic level, indicating a better selectivity for alpha2-presynaptic sites. The pre- and postsynaptic alpha2-adrenoceptors have a different affinity for the two enantiomers of idazoxan. Although the stereoisomers are closely related structurally, ( )-idazoxan possesses a stronger affinity for presynaptic sites. This stereoselectivity was less evident for postsynaptic sites. In rats and dogs, both enantiomers antagonized the sympathoinhibitory effects of clonidine. In rats, ( )- idazoxan was 4-7 times more potent than (-)- idazoxan and 3-8 times more than (-)- idazoxan in dogs. A same order of potency was observed against the sedative effects of clonidine and azepexole in chicks, ( )- idazoxan being 8 times more potent than (-)- idazoxan. Although ( )- idazoxan was more potent than (-) idazoxan, binding studies revealed (-)- idazoxan to be more selective than ( )- idazoxan at central sites. It is concluded that ( )- idazoxan antagonizes both alpha-1 and alpha-2 adrenoceptors and (-)- idazoxan is selective for alpha-2 adrenoceptors. ( )- idazoxan is equipotent for antagonizing postsynaptic alpha-I and alpha-2 adrenoceptors. It is also a potent alpha-2 antagonist at presynaptic and central sites and is 4-8 times more potent than (-)- idazoxan but less selective.

Idazoxan is an alpha2 receptor antagonist which also shows activity at imidazoline I1 and I2 receptors and modulates the release of dopamine. Idazoxan was in phase II development in the US. Later the development of idazoxan for schizophrenia was discontinued. It was also in clinical trials for cognition disorders in United Kingdom, and was also discontinued. Idazoxan is used in scientific research as a tool for the study of alpha 2-adrenoceptors. Idazoxan`s diastereoisomers possess different relative selectivity for alpha2- pre- and postsynaptic receptors: (+)-idazoxan was 7-8 times more potent than (-)-idazoxan in inhibiting p-[3H]aminoclonidine binding, and 40 times more active in antagonizing clonidine at presynaptic level, indicating a better selectivity for alpha2-presynaptic sites. The pre- and postsynaptic alpha2-adrenoceptors have a different affinity for the two enantiomers of idazoxan. Although the stereoisomers are closely related structurally, (+)-idazoxan possesses a stronger affinity for presynaptic sites. This stereoselectivity was less evident for postsynaptic sites. In rats and dogs, both enantiomers antagonized the sympathoinhibitory effects of clonidine. In rats, (+)- idazoxan was 4-7 times more potent than (-)- idazoxan and 3-8 times more than (-)- idazoxan in dogs. A same order of potency was observed against the sedative effects of clonidine and azepexole in chicks, (+)- idazoxan being 8 times more potent than (-)- idazoxan. Although (+)- idazoxan was more potent than (-) idazoxan, binding studies revealed (-)- idazoxan to be more selective than (+)- idazoxan at central sites. It is concluded that (+)- idazoxan antagonizes both alpha-1 and alpha-2 adrenoceptors and (-)- idazoxan is selective for alpha-2 adrenoceptors. In the pithed rat, only (-)- idazoxan possesses both alpha-1 and alpha-2 agonistic effects.

L-152804 is a nonpeptide, potent, selective and orally available antagonist of a neuropeptide-Y Y5 receptor (NPY Y5). L-152,804 may attenuate drug-induced behavioral effects in vivo. L-152,804 prominently decreased nose-poking for the peak dose of cocaine and shifted the dose-response curve for cocaine downward in self-administration animal model of cocaine addiction-related behavior. Cocaine failed to increase c-fos expression in the nucleus accumbens and striatum of L-152,804-treated mice, indicating that the Y5 antagonist could act by influencing neural activity in these regions. Accordingly, the cocaine-induced increase in accumbal extracellular dopamine was attenuated by L- 152,804 and in Y5-KO mice, suggesting that Y5 antagonism influences cocaine-induced behavior by regulating dopamine. L-152,804 significantly reduced both the dosage of self-administered ethanol and the total number of ethanol-reinforced responses in a rodent genetic animal model of alcoholism. The most likely mechanism by which L-152,804 might have decreased g/kg ethanol intake in both behavioral models is by attenuation of its reinforcing properties. This was evidenced by reduced ethanol-reinforced responding in the absence of changes in response onset, which suggests that the NPY Y5 antagonist did not alter neurobiological processes that control the onset of ethanol responding but inhibited responding once it was initiated.

CO-102862, also known as V102862, is a potent, broad-spectrum state-dependent blocker of mammalian voltage-gated sodium channels. A key feature of the mechanism of inhibition is that V102862 has up to 80-fold higher affinity for inactivated Na channels as compared to channels in resting states. V102862 is an orally active anticonvulsant with robust activity in a variety of rodent models of epilepsy.