Multiple Possibilities for the Development of New Anti-depressants WAY SSRI (- 5-HTIB 5-HTIA (-) Ht, NE NE (-) TRYP 5-HTP5-HT ATP CAMP (+) 5-HT3DA DA 5-HT Napamezole BI propion
Multiple Possibilities for the Development of New Anti-depressants 5-HT SSRI 5-HT3 Napamezole DA NE T E G 5-HT ATP cAMP 5-HT? 5-HTP 5-HT1A TRYP (-) WAY 5-HT1B 5-HT1D Anti -depressant Actions (-) (-) a1 a2 Bupropion (-) (+) NE (+) DA (-) (-) (-) 11
Animal Models for Depression Studies Learned helplessness (increase escape behavior) Forced swim/behavioral despair(increase the latency) Tail suspension test (increase the latency) Chick isolation(increase the latency) Olfactory bulbectomy(increase learning and memory) Differential reinforcement of low rates of response(DRL) 5-HTP induced head twitch(increase response) Aggression behaviors(attenuate aggression) Amphetamine self-administration(reduce response Activity wheel stress(reduce response 12
Animal Models for Depression Studies Learned helplessness (increase escape behavior) Forced swim/behavioral despair (increase the latency) Tail suspension test (increase the latency) Chick isolation (increase the latency) Olfactory bulbectomy (increase learning and memory) Differential reinforcement of low rates of response (DRL) 5-HTP induced head twitch (increase response) Aggression behaviors (attenuate aggression) Amphetamine self-administration (reduce response) Activity wheel stress (reduce response) 12
Drug Development Process (1). Discovery Stage (2). Pre-clinical Stage (3). Clinical Stage (4). Marketing Stage 13
Drug Development Process (1). Discovery Stage (2). Pre-clinical Stage (3). Clinical Stage (4). Marketing Stage 13
Major Steps in Pre-clinical Stage General pharmacological studies Effects on various systems for safety evaluation Comprehensive PK studies Absorption, distribution, metabolism and excretion(ADME Formulation development Further improve PK profiles of the final candidates Scale-up and stability Prepare large quantity of the compounds for safety studies Acute and chronic animal toxicological studies 14
Major Steps in Pre-clinical Stage General pharmacological studies • Effects on various systems for safety evaluation Comprehensive PK studies • Absorption, distribution, metabolism and excretion (ADME) Formulation development • Further improve PK profiles of the final candidates Scale-up and stability • Prepare large quantity of the compounds for safety studies Acute and chronic animal toxicological studies 14
Pre-clinical Safety and Toxicological Studies (A). Safety Pharmacology Studies (1)General pharmacology on major systems (2)CNS safety (3CV safety hERG, APD, anaesthetized dog, dog telemetric study (4)Gl motility (5).Genetic Cytogenicity, Ames, mutagenic, etc. (B). Toxicology Studies (1) Study duration Acute 1 day 1 wk 4 wks Chronic 12 wks 6 mons 12 mons 2 years (2)Animal species Rat Mouse Dog Monkey (3)Doses 2-4 doses (4)Administration route Usually oral, but sometimes ip, iv (5)Goals To determine NOAEL, motility clinical pathology, histopathology, etc 15
Pre-clinical Safety and Toxicological Studies (A). Safety Pharmacology Studies (1) General pharmacology on major systems (2) CNS safety (3) CV safety hERG, APD, anaethetized dog, dog telemetric study (4) GI motility (5). Genetic Cytogenicity, Ames, mutagenic, etc. (B). Toxicology Studies (1). Study duration Acute 1 day 1 wk 4 wks Chronic 12 wks 6 mons 12 mons 2 years (2) Animal species Rat Mouse Dog Monkey (3) Doses 2 – 4 doses (4) Administration route Usually oral, but sometimes ip, iv (5) Goals To determine NOAEL, motility, clinical pathology, histopathology, etc. 15