ABSTRACT
Objectives The study aims to document the strategies used to facilitate the engagement of participating receiving assertive community treatment (ACT) to a group cognitive-behavioral therapy for psychosis (CBTp) given for the first time in that context, and to describe the feasibility of this intervention with these consumers and the involved clinicians.Methods A group CBTp of 24 sessions has been delivered. Participants were recruited from both teams ACT of Laval, Quebec. Different strategies were elaborated and documented in order to promote participants' engagement to the therapy. Participants had to fill in the following questionnaires: Self-Esteem Rating Scale - Short Form; Brief Symptom Inventory; and Social Provision Scale before and after the therapy.Results The descriptive data show that the strategies from the Positive reinforcement category were the most used, closely followed by Materials and services, and then by the strategies that aim to compensate Memory problems. Participants showed up on average at 76% of the sessions. Four participants on eight had an improvement on their global self-esteem score, 3 improved on social support and 3 improved their global severity index of the BSI symptoms.Conclusion The information gathered could be very important for other ACT teams that wished to carry out a CBTp among the targeted customer base. These consumers could particularly benefit from this group CBTp considering it could diminish social isolation and marginalization often lived by individuals with severe mental illness.
ABSTRACT
High-throughput screening of Tranzyme Pharma's proprietary macrocycle library using the aequorin Ca2+-bioluminescence assay against the human ghrelin receptor (GRLN) led to the discovery of novel agonists against this G-protein coupled receptor. Early hits such as 1 (Ki=86 nM, EC50=134 nM) though potent in vitro displayed poor pharmacokinetic properties that required optimization. While such macrocycles are not fully rule-of-five compliant, principally due to their molecular weight and clogP, optimization of their pharmacokinetic properties proved feasible largely through conformational rigidification. Extensive SAR led to the identification of 2 (Ki=16 nM, EC50=29 nM), also known as ulimorelin or TZP-101, which has progressed to phase III human clinical trials for the treatment of postoperative ileus. X-ray structure and detailed NMR studies indicated a rigid peptidomimetic portion in 2 that is best defined as a nonideal type-I' ß-turn. Compound 2 is 24% orally bioavailable in both rats and monkeys. Despite its potency, in vitro and in gastric emptying studies, 2 did not induce growth hormone (GH) release in rats, thus demarcating the GH versus GI pharmacology of GRLN.
Subject(s)
Macrocyclic Compounds/chemical synthesis , Peptidomimetics/chemical synthesis , Receptors, Ghrelin/agonists , Administration, Oral , Animals , Biological Availability , Caco-2 Cells , Cell Membrane Permeability , Crystallography, X-Ray , Growth Hormone/metabolism , Humans , In Vitro Techniques , Macaca fascicularis , Macrocyclic Compounds/pharmacokinetics , Macrocyclic Compounds/pharmacology , Magnetic Resonance Spectroscopy , Male , Microsomes, Liver/metabolism , Oligopeptides/chemical synthesis , Oligopeptides/pharmacokinetics , Oligopeptides/pharmacology , Peptidomimetics/pharmacokinetics , Peptidomimetics/pharmacology , Protein Conformation , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A new method for solid phase parallel synthesis of chemically and conformationally diverse macrocyclic peptidomimetics is reported. A key feature of the method is access to broad chemical and conformational diversity. Synthesis and mechanistic studies on the macrocyclization step are reported.
Subject(s)
Chemistry, Pharmaceutical/methods , Peptides, Cyclic/chemistry , Combinatorial Chemistry Techniques , Dimerization , Dipeptides , Models, Chemical , Models, Molecular , Molecular Conformation , Molecular Mimicry , Molecular Structure , Peptides/chemistry , Silver/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A novel class of macrocyclic peptidomimetics was identified and optimized as potent antagonists to the human motilin receptor (hMOT-R). Well-defined structure-activity relationships allowed for rapid optimization of potency that eventually led to high affinity antagonists to hMOT-R. Potency and antagonist functional activity were confirmed both in functional and cell-based assays, as well as on isolated rabbit intestinal smooth muscle strips. Rapid access to this novel class of macrocyclic target structures was made possible through two efficient and complementary solid-phase parallel synthetic approaches, both of which are reported herein.
Subject(s)
Macrocyclic Compounds/chemical synthesis , Oligopeptides/chemical synthesis , Receptors, Gastrointestinal Hormone/antagonists & inhibitors , Receptors, Neuropeptide/antagonists & inhibitors , Animals , CHO Cells , Cricetinae , Cricetulus , Duodenum/drug effects , Duodenum/physiology , Humans , In Vitro Techniques , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacology , Molecular Mimicry , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Oligopeptides/chemistry , Oligopeptides/pharmacology , Rabbits , Radioligand Assay , Structure-Activity RelationshipABSTRACT
[reaction: see text]. A two-step synthesis of N-protected unsaturated amino alcohols is disclosed that relies on an unexpectedly selective cross-metathesis (CM) involving allyl cyanide and pent-4-en-1-ol. The solution concentration and the identity of the Ru complex used are critical to the selectivity and efficiency of CM reactions. The intermediate obtained by CM is converted efficiently to the final desired products through a one-pot nitrile reduction/amine protection procedure.
