Worldwide, there are plants known as psychoactive plants that naturally contain psychedelic active components. They have a high concentration of neuroprotective substances that can interact with the nervous system to produce psychedelic effects. Despite these plants' hazardous potential, recreational use of them is on the rise because of their psychoactive properties. Early neuroscience studies relied heavily on psychoactive plants and plant natural products (NPs), and both recreational and hazardous NPs have contributed significantly to the understanding of almost all neurotransmitter systems. Worldwide, there are many plants that contain psychoactive properties, and people have been using them for ages. Psychoactive plant compounds may significantly alter how people perceive the world.
1. Eur J Med Chem. 2018 May 10;151:27-38. doi: 10.1016/j.ejmech.2018.03.052. Epub 2018 Mar 23. Design, synthesis and bioevaluation of 1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylic acid derivatives as potent neuroprotective agents. Zhang L(1), Zhao Y(1), Wang J(1), Yang D(1), Zhao C(1), Wang C(2), Ma C(3), Cheng M(4). Author information: (1)Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China. (2)Department of Pharmacy, General Hospital of Shenyang Military Area Command, 83 Wenhua Road, Shenhe District, Shenyang, 110840, PR China. (3)Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China. Electronic address: machao_syphu@163.com. (4)Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China. Electronic address: mscheng@syphu.edu.cn. Diverse of 1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylic acid derivatives were designed, synthesized and evaluated for their neuroprotective activity against NMDA-induced cytotoxicity in vitro, and 5q exhibited excellent neuroprotective activity. The compound 5q was selected for further investigation. We found that 5q could attenuate Ca2+ influx induced by NMDA, meanwhile, 5q could suppress the NR2B up-regulation and increase p-ERK1/2 expression. The molecular docking results showed that 5q might fit well in the binding pocket of 4 and interact with some key residues in the binding pocket of 1 simultaneously. Besides, 5q exhibited acceptable metabolic stability. These results suggested that 5q was a promising lead for further development of new potent and orally bioavailable NR2B-selective NMDAR antagonists. Copyright © 2018 Elsevier Masson SAS. All rights reserved. DOI: 10.1016/j.ejmech.2018.03.052 PMID: 29604542 [Indexed for MEDLINE] 2. J Nat Med. 2018 Mar;72(2):582-587. doi: 10.1007/s11418-018-1187-9. Epub 2018 Feb 21. Allergy-preventive effects of linarinic acid and its tetrahydropyrrolo[2,1-b]quinazoline derivatives isolated from Linaria vulgaris. Ma C(1), Higashi N(2), Ishiguro K(2), Zhao Y(1), Zhang L(1), Zhao C(1), Cheng M(1), Oku H(3). Author information: (1)Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, China. (2)School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien Kuban-cho, Nishinomiya, Hyogo, 663-8179, Japan. (3)School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien Kuban-cho, Nishinomiya, Hyogo, 663-8179, Japan. fmoto@mukogawa-u.ac.jp. Linarinic acid, (-)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylic acid (4a), was isolated from the ethanol extract of Linaria vulgaris Mill. In our previous study, a series of tetrahydropyrrolo[2,1-b]quinazoline derivatives 4b, 4c, 5a, 5b, 6a and 6b that were structurally related to 4a and evaluated as neuroprotective agents were synthesized. The aim of the present study was to investigate the novel features of these compounds. We examined their allergy-preventive effects using an in vivo assay system we developed previously, that monitors a decrease in blood flow in the tail vein of mice subjected to sensitization with hen egg-white lysozyme. We observed that 4a and its three derivatives, amide (6a), ester (5a), bromine (4b), and alcohol substituent (6b), showed significant allergy-preventive activities. The study confirmed the allergy-preventive activity of tetrahydropyrrolo[2,1-b]quinazoline derivatives by comprehensively monitoring the specific blood flow decrease occurring in the induction phase of allergy. This finding may aid in the development of new agents for the treatment of allergic diseases such as atopic dermatitis, allergic asthma, and hay fever. DOI: 10.1007/s11418-018-1187-9 PMID: 29468577 [Indexed for MEDLINE] 3. Physiol Behav. 2016 Oct 15;165:383-91. doi: 10.1016/j.physbeh.2016.08.022. Epub 2016 Aug 24. The dual-acting AChE inhibitor and H3 receptor antagonist UW-MD-72 reverses amnesia induced by scopolamine or dizocilpine in passive avoidance paradigm in rats. Sadek B(1), Khan N(2), Darras FH(3), Pockes S(3), Decker M(4). Author information: (1)Department of Pharmacology and Therapeutics, College of Medicine & Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates. Electronic address: bassem.sadek@uaeu.ac.ae. (2)Department of Pharmacology and Therapeutics, College of Medicine & Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates. (3)Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany. (4)Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany; Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius-Maximilian University of Würzburg, Am Hubland, D-97074 Würzburg, Germany. Both the acetylcholine esterase (AChE) and the histamine H3 receptor (H3R) are involved in the metabolism and modulation of acetylcholine release and numerous other centrally acting neurotransmitters. Hence, dual-active AChE inhibitors (AChEIs) and H3R antagonists hold potential to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting AChEI and H3R antagonist 7-(3-(piperidin-1-yl)propoxy)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (UW-MD-72) shows excellent selectivity profiles over the AChE's isoenzyme butyrylcholinesterase (BChE) as well as high and balanced in-vitro affinities at both AChE and hH3R with IC50 of 5.4μM on hAChE and hH3R antagonism with Ki of 2.54μM, respectively. In the current study, the effects of UW-MD-72 (1.25, 2.5, and 5mg/kg, i.p.) on memory deficits induced by the muscarinic cholinergic antagonist scopolamine (SCO) and the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (DIZ) were investigated in a step-through type passive avoidance paradigm in adult male rats applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. The results observed show that SCO (2mg/kg, i.p.) and DIZ (0.1mg/kg, i.p.) significantly impaired learning and memory in rats. However, acute systemic administration of UW-MD-72 significantly ameliorated the SCO- and DIZ-induced amnesic effects. Furthermore, the ameliorating activity of UW-MD-72 (1.25mg/kg, i.p.) in DIZ-induced amnesia was partly reversed when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL, 10mg/kg, i.p.), but not with the CNS penetrant H1R antagonist pyrilamine (PYR, 10mg/kg, i.p.). Moreover, ameliorative effect of UW-MD-72 (1.25mg/kg, i.p.) in DIZ-induced amnesia was strongly reversed when rats were pretreated with a combination of ZOL (10mg/kg, i.p.) and SCO (1.0mg/kg, i.p.), indicating that these memory enhancing effects were, in addition to other neural circuits, observed through histaminergic H2R as well as muscarinic cholinergic neurotransmission. These results demonstrate the ameliorative effects of UW-MD-72 in two in-vivo memory models and provide evidence for the potential of dual-acting AChEI and H3R antagonists to treat cognitive disorders. Copyright © 2016 Elsevier Inc. All rights reserved. DOI: 10.1016/j.physbeh.2016.08.022 PMID: 27568232 [Indexed for MEDLINE] 4. Behav Brain Res. 2016 Jan 15;297:155-64. doi: 10.1016/j.bbr.2015.10.022. Epub 2015 Oct 20. The dual-acting H3 receptor antagonist and AChE inhibitor UW-MD-71 dose-dependently enhances memory retrieval and reverses dizocilpine-induced memory impairment in rats. Khan N(1), Saad A(1), Nurulain SM(1), Darras FH(2), Decker M(3), Sadek B(4). Author information: (1)Department of Pharmacology and Therapeutics, College of Medicine & Health Sciences, P.O. Box 17666, Al Ain 0097, United Arab Emirates University, United Arab Emirates. (2)Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany. (3)Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany; Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius-Maximilian University Würzburg, Am Hubland, D-97074 Würzburg, Germany. (4)Department of Pharmacology and Therapeutics, College of Medicine & Health Sciences, P.O. Box 17666, Al Ain 0097, United Arab Emirates University, United Arab Emirates. Electronic address: bassem.sadek@uaeu.ac.ae. Both the histamine H3 receptor (H3R) and acetylcholine esterase (AChE) are involved in the regulation of release and metabolism of acetylcholine and several other central neurotransmitters. Therefore, dual-active H3R antagonists and AChE inhibitors (AChEIs) have shown in several studies to hold promise to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting H3R antagonist and AChEI 7-(3-(piperidin-1-yl)propoxy)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline (UW-MD-71) with excellent selectivity profiles over both the three other HRs as well as the AChE's isoenzyme butyrylcholinesterase (BChE) shows high and balanced in vitro affinities at both H3R and AChE with IC50 of 33.9nM and hH3R antagonism with Ki of 76.2nM, respectively. In the present study, the effects of UW-MD-71 (1.25-5mg/kg, i.p.) on acquisition, consolidation, and retrieval in a one-trial inhibitory avoidance task in male rats were investigated applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. Furthermore, the effects of UW-MD-71 on memory deficits induced by the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (DIZ) were tested. Our results indicate that administration of UW-MD-71 before the test session dose-dependently increased performance and enhanced procognitive effect on retrieval. However neither pre- nor post-training acute systemic administration of UW-MD-71 facilitated acquisition or consolidation. More importantly, UW-MD-71 (2.5mg/kg, i.p.) ameliorated the DIZ-induced amnesic effects. Furthermore, the procognitive activity of UW-MD-71 in retrieval was completely reversed and partly abrogated in DIZ-induced amnesia when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL), but not with the CNS penetrant H1R antagonist pyrilamine (PYR). These results demonstrate the procognitive effects of UW-MD-71 in two in vivo memory models, and are to our knowledge the first demonstration in vivo that a potent dual-acting H3R antagonist and AChEI is effective in improving retrieval processes in the one-trial inhibitory avoidance task and provide evidence to such compounds to treat cognitive disorders. Copyright © 2015 Elsevier B.V. All rights reserved. DOI: 10.1016/j.bbr.2015.10.022 PMID: 26467607 [Indexed for MEDLINE] 5. Arch Pharm (Weinheim). 2012 Jun;345(6):423-30. doi: 10.1002/ardp.201100424. Epub 2012 Mar 22. Synthesis and biological evaluation of (--)-linarinic acid derivatives as neuroprotective agents against OGD-induced cell damage. Tian Y(1), Ma C, Feng L, Zhang L, Hao F, Pan L, Cheng M. Author information: (1)Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, China. A series of novel (-)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylic acid derivatives were designed and synthesized. All of the prepared compounds were screened for their neuroprotective effects using an in vitro oxygen glucose deprivation (OGD) model of ischemic stroke. Some of the target compounds exhibited moderate to excellent protective potency. In particular, compounds 9d, 9e, 9g, and 9h showed significant protective effects in the SH-SY(5) Y cell line at all three concentrations tested. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. DOI: 10.1002/ardp.201100424 PMID: 22441681 [Indexed for MEDLINE]