2,5-Dimethoxy-4-substituted phenylisopropylamines and phenethylamines are 5-hydroxytryptamine (serotonin) (5-HT) 2A/2C agonists. The former are partial to full agonists, whereas the latter are partial to weak agonists. However, most data come from studies analyzing phospholipase C (PLC)-mediated responses, although additional effectors [e.g., phospholipase A 2 (PLA 2 )] are associated with these receptors. We compared two homologous series of phenylisopropylamines and phenethylamines measuring both PLA 2 and PLC responses in Chinese hamster ovary-K1 cells expressing human 5-HT 2A or 5-HT 2C receptors. In addition, we assayed both groups of compounds as head shake inducers in rats. At the 5-HT 2C receptor, most compounds were partial agonists for both pathways. Relative efficacy of some phenylisopropylamines was higher for both responses compared with their phenethylamine counterparts, whereas for others, no differences were found. At the 5-HT 2A receptor, most compounds behaved as partial agonists, but unlike findings at 5-HT 2C receptors, all phenylisopropylamines were more efficacious than their phenethylamine counterparts. 2,5-Dimethoxyphenylisopropylamine activated only the PLC pathway at both receptor subtypes, 2,5-dimethoxyphenethylamine was selective for PLC at the 5-HT 2C receptor, and 2,5-dimethoxy-4-nitrophenethylamine was PLA 2 -specific at the 5-HT 2A receptor. For both receptors, the rank order of efficacy of compounds differed depending upon which response was measured. The phenylisopropylamines were strong head shake inducers, whereas their phenethylamine congeners were not, in agreement with in vitro results and the involvement of 5-HT 2A receptors in the head shake response. Our results support the concept of functional selectivity and indicate that subtle changes in ligand structure can result in significant differences in the cellular signaling profile.

Archeological studies in the United States, Mexico, and Peru suggest that mescaline, as a cactus constituent, has been used for more than 6000 years. Although it is a widespread cactus alkaloid, it is present in high concentrations in few species, notably the North American peyote ( Lophophora williamsii) and the South American wachuma ( Trichocereus pachanoi, T. peruvianus, and T. bridgesii). Spanish 16th century chroniclers considered these cacti "diabolic", leading to their prohibition, but their use persisted to our days and has been spreading for the last 150 years. In the late 1800s, peyote attracted scientific attention; mescaline was isolated, and its role in the psychedelic effects of peyote tops or "mescal buttons" was demonstrated. Its structure was established by synthesis in 1929, and alternative routes were developed, providing larger amounts for pharmacological and biosynthetic research. Although its effects are attributed mainly to its action as a 5-HT serotonin receptor agonist, mescaline binds in a similar concentration range to 5-HT and α receptors. It is largely excreted unchanged in human urine, and its metabolic products are apparently unrelated to its psychedelic properties. Its low potency is probably responsible for its relative neglect by recreational substance users, as the successful search for structure-activity relationships in the hallucinogen field focused largely on finding more potent analogues. Renewed interest in the possible therapeutic applications of psychedelic drugs may hopefully lead to novel insights regarding the commonalities and differences between the actions of individual classic hallucinogens.

The access pathway to the binding sites for large competitive antagonists of the nicotinic acetylcholine receptor from Torpedo californica electric tissue was analyzed by binding and photolabeling experiments with a-neurotoxins. Binding assays with [ 125 I]a-bungarotoxin showed an increase in the number of accessible binding sites upon stepwise solubilization of the receptor-rich membranes. Similarily, ligand binding is facilitated upon fluidization of the membrane by increasing the temperature. The access to the binding sites seems to be stericallỳ hindered' in the densely packed membrane state. Using a novel series of large biotinylated photoactivatable derivatives of neurotoxin II, we observed that the accessibility to the a/g-but not to the a/d-binding site was considerably decreased for some derivatives under native conditions. This effect was less apparent at higher temperatures and could be abolished by complete solubilization. These observations support the nonequivalence of the receptor's binding sites. Together, our data suggest (a) that a-neurotoxins approach their binding sites from the membrane-facing periphery of the receptor's extramembrane domain rather than through the channel mouth and (b) that different entrance pathways to each binding site exist which vary in their sensitivity to the physical state of the plasma membrane.Keywords: nicotinic acetylcholine receptor; binding sites; a-neurotoxin; membrane fluidity; photoaffinity labeling.The nicotinic acetylcholine receptor (nAChR) from Torpedo californica electric tissue is a heteropentameric protein which consists of five subunits with the stoichiometry a 2 bgd [1,2]. These polypeptide chains span the postsynaptic membrane four times and are arranged in the order a H ga L db clockwise around a central ion channel (the suffixes`H' and`L' indicate the high and low affinity binding sites, respectively, for the antagonist (+/±)-tubocurarine [3]). The two binding sites for agonists and competitive antagonists are located at the interfaces between the a and g and the a and d chains [4±6].Using photolabeling experiments, several individual amino acid residues were identified as part of the binding domain of the a-subunit [7±10]. Several loops of the subunits' polypeptide chains containing several aromatic amino acid residues and the disulfide bond between a-Cys192 and a-Cys193 form a contiguous surface of the ligand binding pockets [11]. Due to the different environments of the two a-subunits, the binding sites are not equivalent. The first 200 amino acids of the a-subunit contribute to the formation of the binding sites for agonists and competitive antagonists: the region closer to the N-terminus appears to be critical for adequate binding of some low molecular competitive antagonists such as dTC, as shown recently [12]. The region closer to the first transmembrane segment M1 (concentrated around residues 180±200) should be also important for adequate binding of larger competitive antagonists, such as a-neurotoxins [13,14]. In addition, individual n...

Prenatally malnourished rats develop hypertension in adulthood, in part through increased α1-adrenoceptor-mediated outflow from the paraventricular nucleus (PVN) to the sympathetic system. We studied whether both α1-adrenoceptor-mediated noradrenergic excitatory pathways from the locus coeruleus (LC) to the PVN and their reciprocal excitatory CRFergic connections contribute to prenatal undernutrition-induced hypertension. For that purpose, we microinjected either α1-adrenoceptor or CRH receptor agonists and/or antagonists in the PVN or the LC, respectively. We also determined the α1-adrenoceptor density in whole hypothalamus and the expression levels of α1A-adrenoceptor mRNA in the PVN. The results showed that: (i) agonists microinjection increased systolic blood pressure and heart rate in normotensive eutrophic rats, but not in prenatally malnourished subjects; (ii) antagonists microinjection reduced hypertension and tachycardia in undernourished rats, but not in eutrophic controls; (iii) in undernourished animals, antagonist administration to one nuclei allowed the agonists recover full efficacy in the complementary nucleus, inducing hypertension and tachycardia; (iv) early undernutrition did not modify the number of α1-adrenoceptor binding sites in hypothalamus, but reduced the number of cells expressing α1A-adrenoceptor mRNA in the PVN. These results support the hypothesis that systolic pressure and heart rate are increased by tonic reciprocal paraventricular–coerulear excitatory interactions in prenatally undernourished young-adult rats.

3,4-methylenedioxymethamphetamine (MDMA; "ecstasy") is a psychoactive drug structurally related to other phenylisopropylamines acting as stimulants or hallucinogens in humans. Although MDMA has a pharmacological identity of its own, the distinction of its acute effects from those of stimulants or even hallucinogens is controversial. In this work, dose-response curves (0.25, 0.5, 1, 3, 5, and 10 mg/kg) representing the acute in vivo effects of MDMA were compared with those of a structurally related stimulant (methamphetamine, MA) and a hallucinogenic analogue (2,5-dimethoxy-4-iodoamphetamine, DOI) in a set of behavioral protocols in rats, including spontaneous psychomotor activity, anxiolytic/anxiogenic-like effects and active avoidance conditioning responses. The behavioral profiles obtained allowed us to differentiate among racemic MDMA, MA, and DOI at different dose ranges. In addition, the evaluation of four MDMA analogues (1, 5, and 10 mg/kg) comprising two well-known MDMA analogues (MDA [3,4-methylenedioxyamphetamine] and MDE (N-ethyl-MDA, believed to substitute for MDMA) and two other structural analogues (MDOH [N-hydroxy-MDA] and MMDA-2 [2-methoxy-4,5-methylenedioxyamphetamine]) showed that none of these exactly resembles MDMA in their pharmacological profiles, highlighting the unique character of this prototypical entactogen. In fact, their effects exhibited similarities with the behavioral profiles of either MA or DOI, as well as novel profiles in specific behavioral paradigms.